Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(O)c1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)c1ccc(OCCCBr)cc1

Procedure:
A solution of ethyl 4-hydroxymandelate (19.6 g, 0.1 mol), 1,3-dibromopropane (60.75 g, 0.3 mol) and cesium carbonate (35.75 g, 0.11 mol) in dry DMF (200 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 1.0 N HCl. The organic layer was washed twice with water, once with brine and then dried over sodium sulfate. The organic layer was then filtered and the solvent remove in vacuo. The resulting oil was chromatographed on silica gel, using a gradient of 100% hexane to methylene chloride/hexane (2:1) to yield the titled compound.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19](C)[CH2:20]CCC(C)C)[CH2:10]1.S(CCCCCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(=O)C)C1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1[OH:39]>>[I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:39])[CH3:20])[CH2:10]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl 6-iodohexyl ether, an equivalent amount of pregn-5-en-20-one-3β-yl 6-iodohexyl ether, there was prepared 6-(pregn-5-en-20-one-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (Step D). TLC data ad Rf values are given in the above Table.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([NH:16][CH2:17][C:18]#[CH:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)C(C)C)(C)C>ClCCl.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]#[C:18][CH2:17][NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a solution of 1-chloro-4-iodobenzene (6.40 g, 26.8 mmol) and N-boc propargylamine (5.00 g, 32.2 mmol) in dichloromethane (117 mL) was added copper (I) iodide (0.204 g, 1.07 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.754 g, 1.07 mmol). The solution was degassed with argon for 10 minutes, then N,N-diisopropylethylamine (14.3 mL, 81.9 mmol) was added and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated, then the residue was diluted with EA and water. The layers were separated and the aqueous layer was extracted twice more with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified using column chromatography on silica gel (80 g Analogix column, gradient hexanes to 20% EA in hexanes over 20 minutes) to give the product (5.97 g, 84%). LCMS: (AA) ES+ 210, 212 (Boc group fragmentation). 1H NMR (400 MHz, d6-DMSO) δ: 7.47-7.39 (m, 4H), 7.35 (s, 1H), 3.97 (d, J=5.6 Hz, 2H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][C:11]2[C:17]([CH3:18])=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[CH3:19])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:35].C([O-])(O)=O.[Na+].[Na+].[Cl-]>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][C:11]2[C:12]([CH3:19])=[CH:13][C:14]([NH:15][C:34](=[O:35])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:16][C:17]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2c(C)cc(N)cc2C)cc1Cc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cc(C)c(Cc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(C)c1
Reaction time: 4 h
Yield: 53.5 %

Procedure:
335 mg (0.96 mmol) of 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylaniline (Example X) and 107 mg (1.06 mmol) of triethylamine are introduced into ml of dichloromethane and, at 0° C., 177 mg (1.29 mmol) of ethoxalyl chloride are added dropwise. The mixture is stirred for 4 h. It is shaken with NaHCO3 solution and NaCl solution, and the organic phase is dried and concentrated in a rotary evaporator. Purification by chromatography (cyclohexane/ethyl acetate=7:1) affords 231 mg of ethyl ({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl}amino)(oxo)-acetate.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:7]=12.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:7]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(C)n(CC2CC2)c2c(Cl)nncc12
Product: Cc1c(C)n(CC2CC2)c2c(OCc3ccccc3)nncc12
Yield: 69.2 %

Procedure:
The title compound was prepared as a white powder in 69.2% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-cyclopropylmethyl-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:23][CH2:22]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: NCC1CCNCC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CN)CC3)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 634.5 %

Procedure:
A mixture of 0.52 g (0.19 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 150 ml acetonitrile, and 0.66 g (5.76 mmole) 4-aminomethylpiperidine [J. Med. Chem., 9 441 (1966)] were stirred at room temperature for four days. The reaction was filtered and the precipitate dissolved in 500 ml of aqueous ammonium hydroxide at pH 10.5. The solution was filtered and the solvent was removed at reduced pressure. The precipitate was washed with 5 ml of water, then ether until dry to give 0.42 g of 7-[4-(aminomethy)-1-piperidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 203°-206° C.
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:26][OH:27])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:20]([N:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:27][CH2:26]2)[C:12]1=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ncccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ncccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a solution 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (1.95 g, 4.70 mmol) in anhydrous tetrahydrofuran (30.0 mL) was added triphenylphosphine (2.06 g, 7.88 mmol) and diisopropyl azodicarboxylate (1.59 g, 7.88 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride (20.0 mL). After the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate (30.0 mL). The organic layer was washed with brine (3×15.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to silica gel column chromatography eluting with ethyl acetate/hexane (35%) to give 1.20 g of yellow solid, which was further purified on HPLC with a reverse phase column to afford the title compound (0.09 g, 8%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.21 (dd, 1H), 7.21-7.12 (m, 2H), 6.50 (s, 1H), 6.07 (s, 1H), 5.83 (d, 1H), 4.88 (s, 2H), 3.88-3.78 (m, 1H), 3.70-3.60 (m, 1H), 1.75-1.65 (m, 2H), 1.37-1.32 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 175.9, 156.4, 152.7, 149.1, 143.9, 142.3, 137.8, 123.4, 117.8, 114.9, 102.6, 101.5, 94.0, 78.3, 58.7, 40.2, 29.0, 27.0, 22.3, 14.0; MS (ES+) m/z 353.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:4](=[O:21])[C:3]=1[C:30](=[O:31])[CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=1
Reactant: O=c1cc(O)c2cccnc2n1-c1cccc([N+](=O)[O-])c1
Reactant: O=C(O)CCc1ccncc1
Product: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Yield: 53.9 %

Procedure:
The procedure of Synthetic Example 1 was repeated using a mixture of 4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2 (1H)-one (2.5 g, 8.83 mmol), 3-(pyridin-4-yl)propionic acid (19.87 g, 131 mmol, 15 eq.; prepared in Synthetic Example 1-(1)) and polyphosphoric acid (about 100 ml) to obtain 4-hydroxy-1-(3-nitrophenyl)-3-[1-oxo-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2 (1H)-one (1.98 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[C:13]1=[O:21].[C:22]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>>[Si:26]([O:20][CH2:19][CH2:18][C:14]1[C:13](=[O:21])[N:12]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
To prepare the compound of the Formula (Ia), 3-bromopyridin-2(1H)-one (III) is reacted with 1-fluoro-2,5-dimethyl-4-nitrobenzene (IV) to give 3-bromo-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (V). Then, (V) is converted with tributylvinyl tin and tetrakis(triphenylphosphine)palladium into 1-(2,6-dimethyl-4-nitrophenyl)-3-vinylpyridin-2(1H)-one (VI). Hydroboration and oxidation of (VI) produces 1-(2,6-dimethyl-4-nitrophenyl)-3-(2-hydroxyethyl)pyridin-2(1H)-one (VII). In order to protect the hydroxy group, (VII) is reacted with tert-butyl(chloro)diphenylsilane in the presence of a base, giving 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (VIII). The reduction of the nitro group in (VIII) leads to 1-(4-amino-2,6-dimethylphenyl)-3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (IX). Then follows the reaction of (IX) with (S)-epoxyphthalimide (X) to give 2-[(2R)-3-({4-[3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}amino)-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione (XI). Ring closure to the oxazolidinone and cleaving off the phthalimide group produces starting from (XI) 1-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,6-dimethylphenyl}-3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (XII), which is reacted with 5-chlorothiophene-2-carbonyl chloride (XIII) to give N-[((5S)-3-{4-[3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chlorothiophene-2-carboxamide (XIV). Cleaving off the protective group in (XIV) produces 5-chloro-N-[((5S)-3-{4-[3-(2-hydroxyethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]thiophene-2-carboxamide (IIa), which is reacted with trans-4-aminohexanol (XV) to give 5-chloro-N-{[(5S)-3-{4-[3-{2-[(trans-4-hydroxycyclohexyl)amino]ethyl}-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl}thiophene-2-carboxamide (Ia).
Reaction SMILES: [CH:1]1([CH2:6]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH:12]=[N:11][C:10]([SH:13])=[N:9]1.C[O-].[Na+]>CO>[NH:8]1[CH:12]=[N:11][C:10]([S:13][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:9]1
Reactant: BrCC1CCCC1
Reactant: Sc1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CCCC2)n[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.3 %

Procedure:
Cyclopentylmethyl bromide (21 g; 0.13 mol) was added in one portion to 1,2,4-triazole-3-thiol (12.3 g; 0.12 mol) and sodium methoxide (7.1 g; 0.13 mol) in dry methanol (100 ml) under dry nitrogen. The mixture was stirred at room temperature for 3 days, refluxed for 3 h and evaporated. The residue was dissolved in ethyl acetate (200 ml) and water (100 ml), the organic phase separated, washed with water (100 ml), dried (Na2SO4), filtered and evaporated, to afford cyclopentylmethyl 1,2,4-triazol-3-yl sulfide (18.1 g; 82%) as a waxy, off-shite solid, m.p. 48°-55° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5](O)=[O:6].[CH3:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=O)=[CH:30][N:29]=1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]2[O:6][C:5]([CH2:4][CH:3]([CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH:11]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=4)[CH2:10]3)[C:2]([F:26])([F:1])[F:25])=[N:35][N:34]=2)=[CH:30][N:29]=1
Reactant: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Reactant: Cc1ccc(C(=O)NN)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nnc(CC(CN3CCCC(c4cccc(C(F)(F)F)c4)C3)C(F)(F)F)o2)cn1
Temperature: 110 °C
Yield: 15.3 %

Procedure:
To a round-bottomed flask (5 ml) was added 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanoic acid (60 mg, 157 μmol), 6-methylnicotinohydrazide (23.7 mg, 157 μmol) and POCl3 (1.64 g, 1 mL, 10.7 mmol). The reaction mixture was heated to reflux at 110° C. for 4 hr. The crude reaction mixture was allowed to cool to room temperature, poured into ice/water and made basic with a saturated solution of Na2CO3. The reaction mixture was extracted with ethyl acetate, washed with brine and H2O, dried over MgSO4, filtered and concentrated. The resultant residue was purified on a silica column (100% hexane to 60% ethyl acetate/hexane gradient) to afford 12 mg (15%) of 2-methyl-5-(5-{3,3,3-trifluoro-2-[3-(3-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-propyl}-[1,3,4]oxadiazol-2-yl)-pyridine as an off-white solid. MH+=499.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[CH:27]=[CH:28][CH:29]=[C:30]([C:31](O)=[O:32])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH:34][CH:35]1[CH2:38][NH:37][CH2:36]1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([N:37]4[CH2:38][CH:35]([OH:34])[CH2:36]4)=[O:32])[C:15]=3[N:14]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: OC1CNC1
Reactant: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)nc3c(C(=O)O)cccc32)c1
Product: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)nc3c(C(=O)N4CC(O)C4)cccc32)c1

Procedure:
4-(3-Hydroxy-azetidine-1-carbonyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 150 mg (0.287 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-4-carboxylic acid and 23.0 mg (0.315 mmol) 3-hydroxy-azetidine. The title compound was obtained as its formiate in form a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]([NH2:32])[C:29]([NH2:33])=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]([NH:38][C:39](=NC(OC)=O)SC)=[O:37]>C(O)(=O)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]6[NH:32][C:39]([NH:38][C:36](=[O:37])[O:35][CH3:34])=[N:33][C:29]6=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(-c2ccc3c(c2)CN(c2ncncc2Cc2ccc(F)cc2)CCO3)nc1N
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ncncc3Cc3ccc(F)cc3)CCO4)nc2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 304.1 %

Procedure:
To a solution of 6-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine (0.200 g, 0.438 mmol) in glacial acetic acid (3 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.117 g, 0.570 mmol). The reaction mixture was stirred at 80° C. for 2 h and then concentrated. Ethyl acetate (100 mL) was added to the residue, and the solution was washed with saturated sodium bicarbonate (50 mL) then dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was taken up in diethyl ether (10 mL) and the resulting precipitate was collected by filtration to give methyl [5-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3H-imidazo[4,5-b]pyridine-2-yl]carbamate (0.70 g, 30% yield) as a brown solid. MS (EI) for C26H25FN6O: 457 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:13]1[C@H:18]([CH3:19])[CH2:17][N:16]([C@H:20]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[C@@H:15]([CH3:41])[CH2:14]1)[CH:11]=[CH2:12].C(N(CC)CC)C>ClCCl>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C@H:20]([N:16]2[CH2:17][C@@H:18]([CH3:19])[N:13]([CH2:10][CH:11]=[CH2:12])[CH2:14][C@@H:15]2[CH3:41])[C:28]2[CH:29]=[CH:30][C:31]([C:32](=[O:33])[N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[CH:39][CH:40]=2)[CH:22]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC(=O)c3ccccc3)c2)C[C@H]1C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Benzoyl chloride (0.33, 2.3 mmol) was added dropwise to a solution of (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (0.92 g, 2.1 mmol) (Example 6) and triethylamine (0.60 mL, 4.2 mmol) in 20 mL dichloromethane. The reaction mixture was stirred for 1 hour and then was washed twice with 20 mL of water, dried over sodium sulfate, and concentrated to dryness. The residue was purified by chromatography on silica gel with dichloromethane:ethanol to give 0.92 g (74%) of (±)-3-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylcarbamoyl)benzyl)phenyl benzoate. NMR (300 MHz, CDCl3): δ 0.9 (d, 3H); 1.2 (d, br t, 9H); 1.9 (t, J=11 Hz, 1H); 2.1 (dd, 1H); 2.5 (br m, 1H); 2.6 (m, 2H); 2.8 (m, 2H); 3.2-3.6 (br m, 5H); 5.2 (2d, 2H); 5.3 (s, 1H); 5.8 (m, 1H); 7-7.2 (2d, s, 3H); 7.3 (m, 3H); 7.5 (m, 4H); 7.6 (t, 1H), 8.2 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:5][CH:4]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:13])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.[BH4-].[Na+]>CO>[CH3:24][C:2]1([CH3:1])[CH2:3][CH:4]([CH:6]([OH:7])[C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:13])=[CH:10][CH:9]=2)[CH2:5]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCNC(=O)c1ccc(C(O)C2CC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
To a flask containing ethyl 3-(4-(3,3-dimethylcyclobutanecarbonyl)benzamido)propanoate (1.21 g, approximately 2.55 mmol pure) was added anhydrous methanol (18.3 mL). The solution was cooled to 0° C. and sodium borohydride (414 mg, 11.0 mmol) was added. After 15 min., the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 1.10 g of crude material. Purification by silica gel flash chromatography (0-50% ethyl acetate in heptane) afforded impure ethyl 3-(4-((3,3-dimethylcyclobutyl)(hydroxy)methyl)benzamido)propanoate (750 mg, approximately 1.8 mmol pure) as an oil. MS (M+1): 334.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8](=[O:21])/[CH:9]=[C:10]2\[S:11][CH:12]=[C:13]([CH3:20])[N:14]\2[CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:32][C:33]([CH3:35])=[O:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8](=[O:21])/[CH:9]=[C:10]2\[S:11][C:12]([C:33]([OH:34])([CH3:35])[CH3:32])=[C:13]([CH3:20])[N:14]\2[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19]2)[CH:7]=1
Reactant: CC(C)=O
Reactant: COc1ccc(Cl)cc1C(=O)/C=C1\SC=C(C)N1CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/C=C1\SC(C(C)(C)O)=C(C)N1CC1CCC1
Temperature: 25 °C

Procedure:
To a solution of Example 169B (140 mg, 4 mmol) in tetrahydrofuran (4 mL) at −78° C. was added lithium diisopropylamide (2 M, 0.6 mL). Acetone (81 μL, 1.2 mmol) was added after 5 min. The reaction was quenched with saturated ammonium chloride (10 mL) after 10 min and the reaction mixture was allowed to warm to room temperature. The reaction was extracted with ethyl acetate (3×10 mL). The organics were combined, washed with brine, dried with sodium sulfate and concentrated. The residue was purified by chromatography over silica gel (dichloromethane-EtOAc 5:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48 (s, 6 H) 1.80-1.93 (m, 4 H) 1.99-2.04 (m, 2 H) 2.35 (s, 3 H) 2.68-2.82 (m, 1 H) 3.86 (s, 3 H) 3.96 (d, J=6.78 Hz, 2 H) 5.49 (s, 1 H) 6.53 (s, 1 H) 7.10 (d, J=8.82 Hz, 1 H) 7.39 (dd, J=8.82, 2.71 Hz, 1 H) 7.63 (d, J=2.71 Hz, 1 H). MS (ESI) m/z 408 (M+H)+. Anal calcd for C21H26ClNO3S.0.7H2O: C, 59.97; H, 6.57; N, 3.33. Found: C, 59.76; H, 6.76; N, 3.02.