Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:26])=[C:11]([C@:13]3([CH3:25])[C:19]([F:21])([F:20])[C:18]([CH3:23])([CH3:22])[O:17][CH2:16][C:15](=O)[NH:14]3)[CH:12]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:26])=[C:11]([C@:13]3([CH3:25])[C:19]([F:21])([F:20])[C:18]([CH3:23])([CH3:22])[O:17][CH2:16][C:15](=[S:36])[NH:14]3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(C3=CCOCC3)ccc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(C3=CCOCC3)ccc2F)C1(F)F
Yield: 86.5 %

Procedure:
The reaction of (R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (72 mg, 195 μmol) with Lawesson's reagent (79 mg, 195 μmol) in 1,4-dioxane (5 ml) yielded the (R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (65 mg, 87% yield) as a white foam. MS (ISP): m/z=386.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:19][CH3:20].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][C:31]#[N:32])=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28](/[C:30](=[CH:13]/[C:12]3[CH:15]=[C:16]([O:17][CH3:18])[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:10]([O:19][CH3:20])[CH:11]=3)/[C:31]#[N:32])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: COc1cc(C=O)cc(OC)c1OCCCCCCO
Reactant: N#CCc1ccc2c(c1)OCO2
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)cc(OC)c1OCCCCCCO
Yield: 95 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(6-hydroxyhexyl)oxy]-3,5-dimethoxyphenyl}prop-2-enenitrile is prepared starting from 4-[(6-hydroxyhexyl)oxy]-3,5-dimethoxybenzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 95% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)=[C:20]=[O:21]>C1COCC1>[N+:28]([C:24]1[CH:23]=[C:22]([NH:19][C:20]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)=[O:21])[CH:27]=[CH:26][CH:25]=1)([O-:30])=[O:29]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc2c(c1)NC(=O)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Cc2ccc(NC(=O)Nc3cccc([N+](=O)[O-])c3)cc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-amino-1,3-dihydro-indol-2-one (0.15 g, 1.0 mmol) and triethylamine (0.30 g, 3.0 mmol) in THF (10 ml) is added 1-isocyanato-3-nitro-benzene (0.16 g, 1.0 mmol). The reaction is stirred at room temperature for 1 hour and the precipitate is collected by vacuum filtration and washed with ethanol to give the desired compound as a light yellow solid. LC-MS: 313.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[S:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:7]=2[CH:6]=1)=[O:4].[C:17]([O:36][NH2:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[S:9][C:10]([C:12](=[O:14])[NH:37][O:36][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2sc(C(=O)O)cc2c1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2sc(C(=O)NOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Temperature: 25 °C

Procedure:
A solution of benzo[b]thiophene-2,5-dicarboxylic acid 5-methyl ester (2.592 g, 10.97 mmol), O-trityl -hydroxylamine (3.020 g, 10.97 mmol), EDC (3.150 g, 16.48 mmol), HOBt (1.482 g, 10.97 mmol) and DIEA (4.80 mL, 27.6 mmol) in anhydrous THF (100 mL) was allowed to stir at rt for one week and then concentrated. To the residue was added MeOH (10 mL) and water (100 mL). The syrup obtained was washed with water (10 mL) and triturated with water (90 mL) to give 2-trityloxycarbamoyl-benzo[b]thiophene-5-carboxylic acid methyl ester as a pale solid. MS (EI): cal'd 243.1 (M-benzothiophene moiety+H+), exp 243.2 (M-benzothiophene moiety+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]2=[O:16])=[N:6][CH:7]=1.C[Sn](C)(C)[C:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH:20]=1.C(OCC)(=O)C.[F-].[K+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:23]1[C:22]2([CH2:27][CH2:28][C:19]([C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[O:10][C:9]4=[O:16])=[N:6][CH:7]=3)=[CH:20][CH2:21]2)[O:26][CH2:25][CH2:24]1
Reactant: COCC1CN(c2ccc(Br)cn2)C(=O)O1
Reactant: C[Sn](C)(C)C1=CCC2(CC1)OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC1CN(c2ccc(C3=CCC4(CC3)OCCO4)cn2)C(=O)O1
Reaction time: 18 h
Yield: 37.5 %

Procedure:
A suspension of 1.4 g of 3-(5-bromo-pyridin-2-yl)-5-methoxymethyl-oxazolidin-2-one, 1.4 g of 8-trimethylstannyl-1,4-dioxa-spiro[4,5]dec-7-ene and 0.3 of bis(triphenylphosphine)palladium(II) dichloride in 20 ml of tetrahydrofuran was stirred at 70° under argon for 18 h. Then, the mixture was cooled, treated with 150 ml of ethyl acetate and 150 ml of saturated potassium fluoride solution and stirred for 30 minutes. The mixture was filtered over a Celite® pad, the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate, concentrated and chromatographed over silica gel 60 with diethyl ether as the eluent. There was obtained 0.6 g of (RS)-3-[5-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-pyridin-2-yl]-5-methoxymethyl-oxazolidin-2-one. 1H-nmr(CDCl3) ppm: 8.41 (s, 1H), 8.03 (d, 1H), 7.89 (d, 1H), 6.08 (t, 1H), 4.82 (m, 1H), 4.21 (t, 1H), 3.91 (t, 1H), 3.92 (s, 4H), 3.60 (m, 2H), 3.32 (s, 3H), 2.54 (m, 2H), 2.38 (m, 2H), 1.82 (t, 2H).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CN(C)C=O.C(N(CC)CC)C.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>Cl>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of glycine tert butyl ester hydrochloride salt (compound of formula XIV, 50 g, 300 mmol) and dimethylformamide (400 ml) at about 0° C. was added triethylamine (127 ml, 885 mmol) and 4-benzyloxybenzenesulfonyl chloride (102 g, 357 mmol). After stirring for about 1 hour, the mixture was warmed to a temperature of about 20° C. to about 25° C., and stirred for about an additional 12 hours. The mixture was diluted with 1M hydrochloric acid, extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ether-hexane afforded 91 g of [4-Benzyloxybenzenesulfonylamino]-acetic acid tert-butyl ester (compound of formula XV) as a colorless solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH:13][C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])=O)=[CH:6][CH:5]=1.Cl>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:14](=[O:15])[NH:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CNC(=O)NNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Temperature: 25 °C

Procedure:
91 ml of a 3N aqueous sodium hydroxide solution were added to 21.43 g (67.93 mmol) of the compound of Example 1A, and the mixture was heated at reflux overnight. After cooling to RT, the mixture was adjusted to pH 1 by slow addition of about 20% strength hydrochloric acid. The precipitated solid was isolated by filtration, washed with water and dried under reduced pressure at 60° C. Yield: 17.55 g (90% of theory, about 88% pure).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:27][O:28][C:29](=[O:77])[NH:30][CH:31]([C:35]([N:37]1[CH:43]([C:44]2[NH:45][C:46]([C:49]3[CH:58]=[CH:57][C:56]4[C:51](=[CH:52][CH:53]=[C:54]([C:59]5[CH:64]=[CH:63][C:62]([C:65]6[NH:66][C:67]([CH:70]7[CH2:74][CH:73]([C:75]#[N:76])[CH2:72][NH:71]7)=[N:68][CH:69]=6)=[CH:61][CH:60]=5)[CH:55]=4)[CH:50]=3)=[CH:47][N:48]=2)[CH2:42][C:39]2([CH2:41][CH2:40]2)[CH2:38]1)=[O:36])[CH:32]([CH3:34])[CH3:33].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]([C:7]([N:71]1[CH2:72][CH:73]([C:75]#[N:76])[CH2:74][CH:70]1[C:67]1[NH:66][C:65]([C:62]2[CH:63]=[CH:64][C:59]([C:54]3[CH:53]=[CH:52][C:51]4[C:56](=[CH:57][CH:58]=[C:49]([C:46]5[NH:45][C:44]([CH:43]6[CH2:42][C:39]7([CH2:41][CH2:40]7)[CH2:38][N:37]6[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:77])[CH:32]([CH3:34])[CH3:33])=[N:48][CH:47]=5)[CH:50]=4)[CH:55]=3)=[CH:60][CH:61]=2)=[CH:69][N:68]=1)=[O:9])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.1 %

Procedure:
2-Methoxycarbonylamino-3,3-dimethyl-butyric acid (43 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(6-{4-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 20, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then brine. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (73 mg, 45%). MS (ESI) m/z 854 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C@@H]1[C@H](OCC2C=CC=CC=2)CN(CC2CC2)[C@]1(C)OCC1C=CC=CC=1)[C:3]1C=CC=CC=1.[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:47][NH:46][C@@H:45]1[CH2:57][O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ClCCO>>[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:47][N:46]([CH2:3][CH2:2][OH:9])[C@@H:45]1[CH2:57][O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1CC1CC1
Agent: Cl
Agent: OCCCl
Product: OCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1

Procedure:
The title compound was prepared as described for compound 8 using (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.51 g, 1.27 mmol) and 2-chloroethanol (0.1 ml, 1.49 mmol) as starting material. (2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethyl-1-(2-hydroxyethyl)pyrrolidine was obtained as a golden oil (0.48 g, yield: 85%).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N#N.[OH-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:19]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCBr
Reactant: OCCOCCOCCOCCO
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOCCOCCOCCOCCO
Temperature: 60 °C

Procedure:
Tetraethyleneglycol (1243 g, 6.40 mol) was heated at 100° C. for 30 minutes with stirring and vigorous N2 bubbling, then cooled to 60° C. A 50% NaOH solution (70.4 g, 0.88 mol) was added and the resulting solution was heated at 100°-105° C. for 30 minutes with N2 bubbling. The solution was cooled to 60° C., bromooctane (154 g, 0.80 mol) was added, and the reaction was heated at 100°-110° C. for 24 hours. The reaction solution was cooled, added to ice water and extracted twice with methylene chloride. The combined extracts were washed with 10% NaOH, water and brine; dried, treated with charcoal, and filtered through a thin silica gel pad. The solvent was removed in vacuo; the residual product (155 g, 63%) was a pale yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10](O)[CH2:11][NH2:12].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1.CO.CC[O:30]CC.CCCCCC>ClCCl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:12][CH:11]([OH:30])[CH2:10][C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH3:24])=[CH:18][CH:17]=1
Reactant: NCC(O)c1cc2ccccc2o1
Reactant: CCOCC
Reactant: COc1ccc(CC(C)=O)cc1
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(CC(C)NC(O)Cc2cc3ccccc3o2)cc1

Procedure:
This compound was prepared in an identical manner to the compound described in Example 2 using 2-(2-benzofuranyl)-2-hydroxyethanamine (1.65 g) and 1-(4-methoxyphenyl)propan-2-one (1.53 g). Chromatography of the residual oil on Kieselgel 60 (4% methanol in dichloromethane) gave the title compound, m.p. 75°-85° (Et2O-hexane) as a 44:56 mixture of diastereoisomers.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([CH3:11])[C:5]=1[O:12][CH3:13])([O-])=O.[H][H].C(OC(=O)C)(=[O:18])C>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:11][OH:18])[C:5]=1[O:12][CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Reactant: COc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: [Pd]
Product: COc1c(N)ccnc1CO

Procedure:
4-Nitro-3-methoxy-2-methylpyridine N-oxide is heated in acetic anhydride and the purified product is deacetylated and reduced with hydrogen and palladium on charcoal to give 4-amino-2-hydroxymethyl-3-methoxypyridine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CC(N(C)C)=O>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of 5-chloro-2-nitrobenzoic acid (13.7 g), piperidine (27 ml) and DMA (100 ml) was stirred and heated to 120° C. for 18 hours. The mixture was evaporated. The residue was dissolved in water and the solution was basified to pH10 by the addition of 2N aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The aqueous layer was acidified to pH2 by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to give 2-nitro-5-piperidinobenzoic acid (16.25 g), m.p.130°-140° C.
Reaction SMILES: [Cl:1]C1C(CC)=NC=C(CC)N=1.[CH:12]1([CH:15]2[NH:20][C:19](=O)[CH:18]([CH:22]3[CH2:24][CH2:23]3)[NH:17][C:16]2=O)[CH2:14][CH2:13]1>>[Cl:1][C:19]1[C:18]([CH:22]2[CH2:24][CH2:23]2)=[N:17][CH:16]=[C:15]([CH:12]2[CH2:14][CH2:13]2)[N:20]=1
Reactant: O=C1NC(C2CC2)C(=O)NC1C1CC1
Reactant: CCc1cnc(CC)c(Cl)n1
Product: Clc1nc(C2CC2)cnc1C1CC1

Procedure:
Following the procedure for the preparation of 3-chloro-2,5-diethylpyrazine but substituting 3,6-dicyclopropylpiperazine-2,5-dione and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 0.99–1.13, 1.94–2.03, 2.38–2.47; MS (ESI+) for C10H11N2 m/z 195 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N+:12]([O-:36])[CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)([OH:22])[CH2:19]1)=[O:17].Cl.[O:38]1CCO[CH2:40][CH2:39]1>CO>[C:39]([O:22][C:20]1([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:21][N:18]([C:16]([C:15]2[CH:14]=[CH:13][N+:12]([O-:36])=[CH:11][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:17])[CH2:19]1)(=[O:38])[CH3:40]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: CO
Product: CC(=O)OC1([C@@H]2CCCCN2)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Yield: 65.6 %

Procedure:
1,1-Dimethylethyl(2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (57 mg, 0.093 mmol) was dissolved in methanol (2 mL) and treated with 4N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at 50° C. for 2.25 hours. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate (35 mg, 0.061 mmol, 66% yield): 1H NMR (400 MHz, d6-DMSO): 7.83 (s, 1H), 7.72 (dt, 2H), 7.55-7.51 (m, 1H), 7.47-7.41 (m, 1H), 7.24 (t, 1H), 4.45-4.32 (m, 1H), 4.14-3.95 (m, 2H), 3.72 (d, 1H), 2.97 (d, 1H), 2.58-2.43 (m, 2H), 1.80-1.73 (m, 1H), 1.67-1.55 (m, 1H), 1.49 (br d, 1H), 1.38-1.16 (m, 2H), 1.16-1.01 (m, 1H); MS (EI) for C20H22FIN4O3: 513 (MH+).
Reaction SMILES: [Mg].[CH2:2]([CH:4]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5]Br)[CH3:3].[CH2:11]([CH:13]([CH2:17][CH2:18]CC)[CH2:14][Mg]Br)[CH3:12].Br[C:22]1C=CC(Br)=C[CH:23]=1>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:3][CH2:2][CH:4]([C:7]1[CH:23]=[CH:22][CH:10]=[CH:9][CH:8]=1)[CH2:5][CH2:14][CH:13]([CH2:17][CH3:18])[CH2:11][CH3:12]
Reactant: CCCCC(CC)CBr
Reactant: Brc1ccc(Br)cc1
Reactant: CCCCC(CC)C[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: CCC(CC)CCC(CC)c1ccccc1
Temperature: 25 °C
Yield: 58 %

Procedure:
A 500 ml two-necked flask equipped with a reflux condenser attached to a nitrogen gas inlet was charged with 10.1 g (0.422 mol) of magnesium turnings. After heating the reaction mixture for 3 minutes under vacuum and cooling it to room temperature, 200 mL of dry Et2O was filled and then 54.3 g (0.281 mol) of 2-ethylhexyl bromide in 50 mL dry ether was added dropwise. The solution was refluxed for 3 hours and cooled to room temperature. The prepared 2-ethylhexylmagnesium bromide solution was added dropwise, over 1 h, to an ice-cooled and stirring mixture of 1,4-dibromobenzene (24.5 g, 0.104 mol) and Ni(dppp)Cl2 (0.564 g, 1.04 mmol) in dry ether (300 mL). The cooling bath was removed and the temperature was increased to room temperature. The reaction solution was then refluxed overnight, cooled to 0° C. and carefully quenched with water (50 mL), followed by 2N HCl (300 mL). After separation of the organic layer, the organic layer was washed with water (300 mL) two times and dried with anhydrous sodium sulfate and evaporated in vacuo. Column chromatography (silica gel, hexane) yielded the pure compound 20a (18.2 g, 58%). 1H NMR (CDCl3): δ 0.84-0.92 (12H, m), 1.25-1.35 (16H, m), 1.50-1.58 (2H, m), 2.50 (4H, d), 7.04 (4H, s). MS (EI): calcd, 302.5. found M+, 302.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][CH:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][NH:13][CH2:12]1>>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([N:13]2[CH2:14][C@H:15]([CH3:17])[CH2:16][C@H:11]([CH3:10])[CH2:12]2)[N:3]=[CH:4][N:5]=1.[Cl:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:14][C@@H:15]([CH3:17])[CH2:16][C@H:11]([CH3:10])[CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CC1CNCC(C)C1
Product: C[C@@H]1C[C@H](C)CN(c2ncnc(Cl)c2F)C1
Product: C[C@H]1C[C@H](C)CN(c2cc(Cl)ncn2)C1
Reaction time: 0.5 h

Procedure:
0.2 g of 4,6-dichloro-5-fluoropyrimidine and 0.41 g of 3,5-dimethylpiperidine (cis/trans diastereomer=about 3/1) were mixed and left for 30 minutes at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.1 g of 4-chloro-6-(cis-3,5-dimethyl piperidino)-5-fluoropyrimidine and 0.05 g of 4-chloro-6-(trans-3,5-dimethylpiperidino)pyrimidin.
Reaction SMILES: [C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[C:8]([CH2:26][CH3:27])=[CH:9][C:10]2[CH:11]3[CH:19]([CH2:20][CH2:21][C:22]=2[CH:23]=1)[CH:18]1[C:14]([CH3:25])([C:15](=O)[CH2:16][CH2:17]1)[CH2:13][CH2:12]3)([CH3:4])([CH3:3])[CH3:2].C(OP([CH2:38][C:39]#[N:40])(=O)OCC)C>>[C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[C:8]([CH2:26][CH3:27])=[CH:9][C:10]2[CH:11]3[CH:19]([CH2:20][CH2:21][C:22]=2[CH:23]=1)[CH:18]1[C:14]([CH3:25])([C:15](=[CH:38][C:39]#[N:40])[CH2:16][CH2:17]1)[CH2:13][CH2:12]3)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CCC1C2CCC2(C)C(=O)CCC12
Reactant: CCOP(=O)(CC#N)OCC
Product: CCc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CCC1C2CCC2(C)C(=CC#N)CCC12
Yield: 56.5 %

Procedure:
The reaction was carried out as described in procedure C using silyl ether 12 (1 g, 2.6 mmol) and diethyl(cyanomethyl)phosphonate (691 mg, 631 μl, 3.9 mmol). Flash column chromatography (SiO2 hexane:ethyl acetate 20:1) afforded the two isomers 24 as a colourless oil (641 mg, 1.47 mmol, 57%). m/z (FAB) 435.3 (M+, 100%); HRMS (FAB+) calcd for C28H41ONSi 435.2957, found 435.2961.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22]([O:26][C:27]1[CH:32]=[C:31]([CH2:33]Cl)[CH:30]=[CH:29][C:28]=1[C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[F:43])[CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[CH2:22]([O:26][C:27]1[CH:32]=[C:31]([CH2:33][O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C@@H:8]3[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=2)[CH:30]=[CH:29][C:28]=1[C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[F:43])[CH2:23][CH2:24][CH3:25].[CH2:22]([O:26][C:27]1[CH:32]=[C:31]([CH2:33][O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C@H:8]3[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=2)[CH:30]=[CH:29][C:28]=1[C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[F:43])[CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)C[C@@H]1CCc2ccc(O)cc21
Reactant: CCCCOc1cc(CCl)ccc1-c1cc(OC)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1cc(COc2ccc3c(c2)[C@@H](CC(=O)OC)CC3)ccc1-c1cc(OC)ccc1F
Product: CCCCOc1cc(COc2ccc3c(c2)[C@H](CC(=O)OC)CC3)ccc1-c1cc(OC)ccc1F
Reaction time: 8 h

Procedure:
To flask containing (R) or (S)-methyl 2-(6-hydroxy-2,3-dihydro-1H-inden-1-yl)acetate (1.5) (0.0100 g, 0.0485 mmol) and cesium carbonate (0.0205 g, 0.0630 mmol) in DMF (1 mL) was added 2-(butyloxy)-4-(chloromethyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl (D) (0.0188 g, 0.0582 mmol). The reaction was then stirred overnight, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (0 to 20% EtOAc/Hexane) to provide methyl ((1R)-6-(((2-(butyloxy)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)-2,3-dihydro-1H-inden-1-yl)acetate or methyl ((1S)-6-(((2-(butyloxy)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)-2,3-dihydro-1H-inden-1-yl)acetate 17.1.