Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[C:18]3[CH:19]=[N:20][N:21]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](O)[N:25]=4)[C:22]=3[CH3:23])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:26]1[N:25]=[C:24]([N:21]2[C:22]([CH3:23])=[C:18](/[CH:17]=[CH:16]/[CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)[CH2:10][CH2:11]3)[CH:19]=[N:20]2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-n2ncc(/C=C/CN3CCN(c4cc(F)cc(F)c4)CC3)c2C)nc(O)n1
Product: Cc1cc(-n2ncc(/C=C/CN3CCN(c4cc(F)cc(F)c4)CC3)c2C)nc(Cl)n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To 250 mg of the compound obtained in Example 34 was added 5 ml of phosphorus oxychloride. The mixture was stirred at 60° C. for 2.5 hours, followed by concentration. A mixture of the concentrate and water was neutralized with sodium hydrogencarbonate and extracted with chloroform three times. The combined organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform was a developing solution. Concentration of the fraction containing the desired compound gave 180 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]([F:10])([F:9])[F:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].OS(O)(=O)=O.O=S(=O)=O>>[F:8][C:7]([F:10])([F:9])[C:1]1[CH:6]=[C:5]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1ccccc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1

Procedure:
The m-trifluoromethylbenzenesulfonyl chloride starting material was prepared by reacting benzotrifluoride with chlorosulfonic acid in the presence of oleum (65% SO3), according to the method described in Chemical Abstracts 75, 19942d, (1971); German Offen. No. 1,954,448.
Reaction SMILES: [Na].[O:2]=[C:3]([CH:25]([CH3:27])[CH3:26])[CH2:4][C:5]([NH:7][C@@H:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][S:14][C@H:9]12)=[O:6].[N:28]([O-])=[O:29].[Na+].Cl>C(OCC)(=O)C.O.C(O)(=O)C>[OH:29][N:28]=[C:4]([C:3](=[O:2])[CH:25]([CH3:27])[CH3:26])[C:5]([NH:7][C@@H:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=N[O-]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CC(=O)C(C)C)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)C(=O)C(C)C)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6.1 g. of sodium salt of 7β-(3-oxo-4-methylvaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid in 60 ml. of glacial acetic acid, are dropped 2.1 g. of sodium nitrite dissolved in 20 ml. of water. After stirring for 2 hours at ambient temperature, there are added 200 ml. of ethyl acetate and 100 ml. of hydrochloric acid 0.1N. The phases are separated and the organic phase is washed with 50 ml. of water, made anhydrous, decolourised over charcoal and concentrated to small volume. The precipitated solid is filtered off to give 1.4 g of 7β-(2-hydroxyimino-3-oxo-4-methylvaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid melting at 156° C. (with decomposition); [α]D =+76.9° C. (c=2 in tetrahydrofuran/water 1:1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.[N-:17]=[N+:18]=[N-:19].[Na+].CN(C=O)C>O>[N:17]([CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1)=[N+:18]=[N-:19]
Reactant: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 18 h
Yield: 76.6 %

Procedure:
Under nitrogen, a solution of 5-(2-bromoethyl)-2-sulfamoylbenzo[b]thiophene (1.2 g, 0.0037 mol), NaN3 (0.6 g, 0.0092 mol) and DMF (25 ml) was heated at 100° C. After 18 hours, the solution was cooled, poured into H2O, and filtered to yield 0.8 g of product. The filtrate was extracted with ethyl acetate (2x). The organic layers were dried, filtered and concentrated to dryness to yield an additional 0.4 g of product (75%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O>[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (157 mg, 0.5 mmole) with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e (150 mg, 0.7 mmole) and Cs2CO3 (673 mg, 2.1 mmole) in a manner as previously described for example 1 to give 51 mg (39%) of a crisp foam. 1H NMR (DMSO-d6) δ 8.54 (1H, dd, J=5.5, 1.13 Hz), 8.05 (1H, s), 7.84 (1H, d, J=8.6 Hz, 7.61–7.55 (1H, m), 7.54 (1H, d, J=2.1 Hz), 7.03(1H, dd, J=2.1, 8.6 Hz), 6.64 (1H, d, J=5.5 Hz), 4.12–3.51 (5H, m), 3.67 (3H, s), 3.27, 3.24 (3H, 2s), 2.80 (3H, d, J=4.5 Hz), 2.60 (3H, s), 2.35–1.95 (2H, m). Anal. Calcd for C25H26N4O4S.0.9 H2O0.2 EtOAc: C, 60.47; H, 5.78; N, 10.93; S, 6.26. Found: C, 60.46; H, 5.56; N, 10.81; S, 6.34.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Br:16])[CH:8]=1)[CH3:2].[Cl-].[NH4+]>C1COCC1.C(O)C.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2=[CH:11][N:10]=[C:9]([Br:16])[CH:8]=[C:7]2[CH:6]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Br)ncc2[nH]1

Procedure:
Route A: To a solution of 3-(2-bromo-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester (Preparation 25, 3.38 g, 10.7 mmol) in THF (50 mL) and ethanol (100 mL) was added saturated ammonium chloride solution (50 mL) and iron powder (3.57 g, 64.0 mmol) and the reaction heated under reflux for 2 h. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The solvent was removed in vacuo and the remainder partitioned between saturated sodium hydrogen carbonate solution (100 mL) and ethyl acetate (3×150 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid. δH (CD3OD): 1.42 (3H, t), 4.43 (2H, q), 7.14 (1H, s), 7.85 (1H, s), 8.58 (1H, s); m/z (ES+)=269 [M+H]+.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1.[CH3:11]I>C(Cl)Cl>[Br:3][C:4]1[S:5][C:6]([CH2:9][O:10][CH3:11])=[CH:7][N:8]=1
Reactant: CI
Reactant: OCc1cnc(Br)s1
Agent: N#N
Solvent: ClCCl
Product: COCc1cnc(Br)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-bromothiazol-5-yl)methanol (WO 2009/077990, p. 92) (1.19 g, 6.11 mmol) in CH2Cl2 (4.0 mL) was treated with MeI (0.46 mL, 7.33 mmol) followed by Ag2O (2.12 g, 9.16 mmol) and the resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a colorless oil: TLC: rf (7:3 hept-EA)=0.33. LC-MS-conditions 07: tR=0.66 min, [M+H]+=209.93.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]([C:23]1[O:27][C:26]([CH3:28])=[C:25]([C:29](Cl)=[O:30])[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[O:27][C:26]([CH3:28])=[C:25]([C:29]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:30])[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)Cl
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: Cc1oc(C(C)(C)C)cc1C(=O)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 29 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 5-tert-butyl-2-methylfuran-3-carbonyl chloride to afford the title compound (25 mg, 29%). 1H-NMR (δ, ppm, DMSO-d6): 1.25 (s, 9H, t-Bu), 3.29 (s, 3H, Me), 6.47 (d, 1H, HPy,5, J=6.0 Hz), 6.64 (s, 1H, Hfur), 6.86 (d, 1H, Harom, J=8.0 Hz), 7.38 (t, 1H, Harom, J=8.0 Hz), 7.57 (t, 1H, Harom, J=2.2 Hz), 7.61 (d, 1H, Harom, J=8.0 Hz), 7.79 (d, 1H, HPy,6, J=6.0 Hz), 9.68 (s, 1H, NHamide), 11.18 (s, 1H, NHPy3), 11.37 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C22H23N4O4: 407.1719; found: 407.1721.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]([CH2:43][O:44][P:45]([O:48][CH2:49][CH2:50][NH2:51])([OH:47])=[O:46])[O:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH3:76]/[C:77](/[CH:89]=[CH:90]/[CH:91]=[C:92](\[CH3:104])/[CH:93]=[CH:94]/[C:95]1[C:100]([CH3:102])([CH3:101])[CH2:99][CH2:98][CH2:97][C:96]=1[CH3:103])=[CH:78]\[CH2:79][O:80][C:81](=[O:88])[CH2:82][CH2:83][CH2:84][C:85](O)=[O:86].C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.CN(C=O)C>[C:1]([O:20][CH2:21][C@@H:22]([O:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][O:44][P:45]([O:48][CH2:49][CH2:50][NH:51][C:85](=[O:86])[CH2:84][CH2:83][CH2:82][C:81]([O:80][CH2:79]/[CH:78]=[C:77](\[CH3:76])/[CH:89]=[CH:90]/[CH:91]=[C:92](\[CH3:104])/[CH:93]=[CH:94]/[C:95]1[C:100]([CH3:101])([CH3:102])[CH2:99][CH2:98][CH2:97][C:96]=1[CH3:103])=[O:88])([OH:47])=[O:46])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/COC(=O)CCCC(=O)O)C(C)(C)CCC1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN)OC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCNC(=O)CCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (500 mg, 0.672 mmol), N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (306.5 mg, 0.806 mmol) and 5-(((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-yl)oxy)-5-oxopentanoic acid (269 mg, 0.672 mmol) was dissolved in chloroform/DMF (10 mL, 1:1 mixture) in an amber-colored vial flushed with argon and N,N-Diisopropylethylamine (300 uL, 1.68 mmol) was added. Reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was concentrated and then purified by silica gel chromatography using a dichloromethane/methanol gradient. The fractions were pooled and concentrated to yield yellowish oil (460 mg, 61%). Verified product by NMR. 1H NMR (400 MHz), δH: 8.6 (d, 1H), 8.27 (d, 1H), 6.57-6.61 (dd, 1H), 6.08-6.25 (m, 4H), 5.57 (t, 1H), 5.30-5.34 (m, 4H), 5.18 (m, 1H), 4.68-4.70 (d, 2H), 4.28-4.35 (m, 1H), 4.05-4.15 (m, 1H), 3.81-3.97 (m, 4H), 3.52-3.62 (m, 1H), 3.35-3.45 (m, 2H), 2.95-3.05 (m, 1H), 2.33-2.35 (t, 3H), 2.2-2.3 (m, 7H), 1.9-2.05 (m, 17H), 1.85 (s, 3H), 1.69 (s, 3H), 1.5-1.65 (m, 6H), 1.4-1.5 (m, 2H), 1.18-1.38 (m, ˜40H), 1.01 (s, 3H), 0.84-0.88 (m, 12H).
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:25][CH:24]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:23]([C@@H:21]([NH:20][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[CH:19]=[CH:18][N:17]=3)[CH3:22])=[CH:24][N:25]=2)=[CH:29][CH:30]=1
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)c1cnc(-c2ccc(Cl)cc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)O)n1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a round bottom flask containing a stir bar and (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (82 mg, 0.16 mmol) was added DCM (1 mL) followed by the addition of TFA (1 mL). Resulting reaction mixture allowed to stir 30 min at RT. The volatiles were then removed and the residue neutralized by the addition of a saturated solution of NaHCO3. The aqueous mixture was then extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a brown foam of (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (61 mg, 0.14 mmol, 84% yield) which was used without further purification. LCMS m/z 446.2 (M+H)+, Rt 0.71 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])(=[N:14][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CS(=O)Nc1ccc(Br)cc1
Product: CCN=S(C)(=O)Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and ethylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.91 min; Mass spectrum (ESI+): m/z=277, 279 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([F:23])=[CH:14][C:15]=3[S:19]([CH3:22])(=[O:21])=[O:20])[C:10]=2[CH2:9][CH2:8][CH2:7]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([C@H:51](O)[CH3:52])=[CH:47][CH:46]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[C:18]2[N:17]([C@H:51]([C:48]3[CH:49]=[CH:50][C:45]([Cl:44])=[CH:46][CH:47]=3)[CH3:52])[C:16]3[C:11](=[CH:12][C:13]([F:23])=[CH:14][C:15]=3[S:19]([CH3:22])(=[O:21])=[O:20])[C:10]=2[CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1CCCc2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Reactant: C[C@@H](O)c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CCCc2c1n([C@@H](C)c1ccc(Cl)cc1)c1c(S(C)(=O)=O)cc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of the compound of Step 4 (1 eq), triphenylphosphine (1.5 eq) and (1R)-1-(4-chlorophenyl)ethanol (1.5 eq, prepared following the general procedure described in Reference Example 1) in THF (0.175M) was added a solution of di-tert-butyl azodicarboxylate (2.1 M in THF, 1.5 eq) over a 10 min period. The mixture was stirred at room temperature for 2 hr and concentrated. The residue was purified by silica gel flash chromatography, eluting with 7% EtOAc in toluene to give the desired product (˜90% pure) which was used as such for the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[C:17]#[N:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=2[C:17]#[N:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2C#N)CC1
Temperature: 105 °C

Procedure:
A mixture of piperazine-1-carboxylic acid tert-butyl ester (1.05 g, 5.65 mmol), 2-bromo-5-fluoro-benzonitrile (1.13 g, 5.65 mmol), Pd2(dba)3 (259 mg, 0.283 mmol), xanthphos (490 mg, 0.848 mmol), sodium tert-butoxide (1.63 g, 16.95 mmol) in anhydrous 1,4-dioxane (10 ml) was heated at 100-110° C. in a sealed tube for 1 h. After cooled to room temperature, the mixture was filtered through celite then concentrated before purified by chromatography (hexanes/EtOAc) to provide compound as indicated (1.31 g, 76%). m/z (M+1) 306.21.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24].Cl.[OH-].[Na+]>O.C(O)C>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(O)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 26.9 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 5-hydroxy-2-methylaniline (36 mg, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and neutralized with aqueous 2N NaOH to pH 6-7. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by column chromatography to give a yellow solid (18 mg, 27%). 1H NMR (Acetone-d6): 9.53-9.51 (m, 1H), 8.85 (s, 1H), 8.71 (dd, J=1.8, 4.8 Hz, 1H), 8.67-8.63 (m, 1H), 8.49 (s, 1H), 7.53-7.48 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.98 (s, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[Si]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]2[CH:33]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:52])([CH3:51])[O:44]C3CCCCO3)[CH:35]=[CH:36][CH:37]=2)[CH:18]=[CH:19][C:20]=1[CH2:21][O:22][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>C1COCC1.O>[OH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]2[CH:33]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:52])([OH:44])[CH3:51])[CH:35]=[CH:36][CH:37]=2)[CH:18]=[CH:19][C:20]=1[CH2:21][OH:22]
Reactant: CC(C)(CCCCCc1cccc(C=Cc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCc1cccc(C=Cc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.56 ml of concentrated sulphuric acid with 2.30 g (3.37 mmol) of 2-[6-(3-{2-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran in 30 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 80-heptane 20), white crystals (m=475 mg; Y=38%) are obtained. m.p.=93-5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][N:10]([CH3:19])[C:11]([CH:13]1[O:18][CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:11]([N:10]([CH3:19])[CH3:9])=[O:12])[CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: CN(C)C(=O)C1CNCCO1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1CN(c2cccc(Br)c2)CCO1
Temperature: 80 °C
Yield: 42.3 %

Procedure:
A mixture of 1,3-dibromobenzene (387 μL, 3.20 mmol), N,N-dimethylmorpholine-2-carboxamide (506 mg, 3.20 mmol), Pd2(dba)3 (73.3 mg, 0.0800 mmol), rac-BINAP (154 mg, 0.240 mmol) and NaOtBu (369 mg, 3.84 mmol) in toluene (8 mL) was heated at 80° C. for 5 hours under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=95:5→90:10→80:20→67:33→50:50) to afford desired product (424 mg, 42.3%) as orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH:9]=1)[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH2:21]([O:23][C:24](=[O:30])[C:25](OCC)=[O:26])[CH3:22].Cl>C(OCC)C.O1CCCC1.O.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5](=[O:10])[CH:6]([C:25](=[O:26])[C:24]([O:23][CH2:21][CH3:22])=[O:30])[CH2:7][CH2:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC1=CCCCC1=O
Agent: Cl
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reaction time: 8 h
Yield: 76 %

Procedure:
41.40 g (0.29 mol) of 2-ethoxycyclohex-2-en-1-one were dissolved in 310 mL of diethyl ether and 325 mL of 1M LiN(TMS)2 in tetrahydrofuran were added dropwise at 50° C. After 30 minutes at the same temperature, 44.2 mL of diethyloxalate were also added under stirring. The solution was kept at room temperature overnight (TLC chloroform). 300 mL of water were then added, the pH adjusted to 4-5 by adding 1N HCl and the resulting solution extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column eluted by chloroform (76% yield as an oil).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]3[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1>>[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]3[CH2:47][CH2:46][CH:45]([N:8]4[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]5[C:24]6[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=6)[N:18]([CH3:31])[N:17]=5)[CH2:9]4)[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(O)C(F)(F)F)ccc21
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(c4ccc5c(c4)OCO5)CC3)C2)c2cc(C(O)C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 60, Step B) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.