Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]2([NH2:11])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:21]([O:25][C:26]([N:28]([CH3:58])[C:29]([C:31]1[C:32]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:33][N:34]2[C:39]([F:40])=[CH:38][C:37]([C:41]3[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=3[CH3:50])[C:44](O)=[O:45])=[CH:36][C:35]=12)=[O:30])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:40][C:39]1[N:34]2[N:33]=[C:32]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[C:31]([C:29]([N:28]([CH3:58])[C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:30])=[C:35]2[CH:36]=[C:37]([C:41]2[CH:42]=[C:43]([C:44](=[O:45])[NH:11][C:8]3([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10][CH2:9]3)[CH:47]=[CH:48][C:49]=2[CH3:50])[CH:38]=1
Reactant: NC1(c2ccccc2)CC1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2(c3ccccc3)CC2)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a solution containing 1-phenylcyclopropanamine hydrochloride (0.010 g, 0.061 mmol), diisopropylethylamine (0.086 mL, 0.49 mmol), 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.032 g, 0.061 mmol) and DMF (0.41 mL) was added HATU (0.047 g, 0.12 mmol) in one portion. The solution was maintained at room temperature for 1 h and concentrated. The resultant residue was purified on silica gel (30-100% ethyl acetate/hexanes, 45 min. gradient) to afford tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a residue. LCMS retention time: 2.938 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 637 (MH+).
Reaction SMILES: [N:1]1C=CC=CC=1C(=O)CC(=O)CC(C1C=CC=CN=1)=O.[N:21]1([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32](=O)[CH2:33][C:34](=[O:49])[CH2:35][C:36]([C:38]3[CH:43]=[C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH:41]=[CH:40][N:39]=3)=O)[CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>CO>[N:21]1([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]3[NH:1][C:36]([C:38]4[CH:43]=[C:42]([N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)[CH:41]=[CH:40][N:39]=4)=[CH:35][C:34](=[O:49])[CH:33]=3)[CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(CC(=O)c1ccccn1)CC(=O)c1ccccn1
Reactant: O=C(CC(=O)c1cc(N2CCCC2)ccn1)CC(=O)c1cc(N2CCCC2)ccn1
Solvent: CO
Product: O=c1cc(-c2cc(N3CCCC3)ccn2)[nH]c(-c2cc(N3CCCC3)ccn2)c1

Procedure:
This compound is prepared in a manner analogous to that described in Example 1, Step 2 for 1,5-di-pyridin-2-yl-pentane-1,3,5-trione, but instead the pyrrolidine-substituted triketone from Example 21 is used. Pure 4,4″-di-pyrrolidin-1-yl-1′H-[2,2′;6′,2″]terpyridin-4′-one can be obtained by recrystallisation from methanol in the form of an almost colourless solid. 1.81–2.05 (m, 8H); 3.17–3.33 (m, 8H); 6.32 (dd, 2H, J=5.7, 2.3 Hz); 6.84 (d, 2H, J=2.3 Hz); 6.90 (s, 2H); 8.19 (d, 2H, J=5.7 Hz). MS (EI pos., 70 eV), m/z=387 ([M+]), 359 (100); 358 (85); 330 (20); 28 (60).
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4](OC)=[O:5].[BH4-].[Li+]>C1COCC1.O>[CH2:11]([O:10][CH2:9][CH2:8][CH:2]([OH:1])[CH2:3][CH2:4][OH:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C[C@@H](O)CCOCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC(O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(S)-hydroxy-5-benzyloxypentanoate (38, Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R., J. Am. Chem. Soc. 1988, 110 629-631) (183 mmol) in anhydrous THF (1 l) is added lithium borohydride (7.7 g, excess) at 0° C. over 15 min. The reaction mixture is stirred at RT for 30 minutes, and then refluxed for 6 hours. The mixture is then cooled to 0° C., diluted with water (60 ml), and stirred overnight at RT. A white precipitate is removed by filtration, the solvent removed in vacuum, and the residue distilled under vacuum to yield 5-benzyloxy-1,3-pentanediol 39.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:38]([CH2:37][O:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:39]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C)cc3)c(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C)cc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-5-p-tolyl-naphthalen-2-ylmethyl)-amide (252 mg, 0.54 mmol), prepared in the previous step, bromoacetonitrile (55 μL, 0.81 mmol) and potassium carbonate (378 mg, 2.73 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced presure to give 2-butyl-benzofuran-3-carboxylic acid (6-cyanomethoxy-5-p-tolyl-naphthalen-2-ylmethyl)-amide (269 mg, 99%) as a light brown solid, mp 114-117° C.
Reaction SMILES: [O:1]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:18]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:18][C:2]1[O:1][C:10]2[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2ccoc2CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)oc2CC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4,5,7,8-tetrahydrofuro[3,2-d]azepine-6-carboxylate (0.21 mmol) in chloroform (0.5 mL) and acetic acid (0.5 mL) is treated with N-bromosuccinimide (0.21 mmol) at RT. After 1 hour, the reaction is poured over saturated aqueous NaHCO3, and extracted with ethyl acetate (2×5 mL). The organic layers are washed with brine, dried, and purified by silica chromatography (20% ethyl acetate/hexanes) to give tert-butyl 2-bromo-4,5,7,8-tetrahydrofuro[3,2-d]azepine-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2nccnc2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc2nccnc2c1)C(=O)OCC
Temperature: 110 °C
Yield: 89.9 %

Procedure:
A mixture of 6-aminoquinoxaline(19.2 g) and diethyl ethoxymethylenemalonate(34.8 g) was heated for an hour at 110° C. After filtration, the crystals thus obtained were crystallized from ethanol to give diethyl N-(6-quinoxalyl)aminomethylenemalonate (37.5 g) as pale yellow needles, m.p. 112°-114° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH2:9](B(CC)CC)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O.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>[CH2:9]([C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1)[CH3:10]
Reactant: Fc1ccc(Br)cn1
Reactant: CCB(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(F)nc1

Procedure:
A mixture of 5-bromo-2-fluoropyridine (2-a, 5.03 g, 28.6 mmol, Lancaster Synthesis, Inc., Wyndham, N.H.), triethylborane (1M in tetrahydrofuran, 42.8 mL, 42.8 mmol), K2CO3 (15.8 g, 114.2 mmol) and Pd(PPh3)4 (1.65 g, 1.43 mmol) in N,N-dimethylformamide was heated at 85 C for 4 h. The reaction mixture was diluted with water and extracted with hexanes. The organic layer was then washed with water (×2), separated, dried (MgSO4), and concentrated in vacuo. Chromatography (50%, CH2Cl2 in hexanes) afforded the desired product (2-b); 1H NMR (500 MHz, CDCl3) δ 8.04 (d, 1 H, J=1.0 Hz), 7.60 (dt, 1 H, J=8.0, 2.5 Hz), 6.85 (dd, 1 H, J=8.3, 2.8 Hz), 2.65 (q, 2 H, J=7.8 Hz), 1.21 (t, 3 H, J=7.7 Hz)
Reaction SMILES: [Si:1]([O:8][C@H:9](C1C=CC(O)=C2C=1C=CC(=O)N2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[CH:27]=[C:28]([S:32]([C:35]3[CH:36]=[C:37]4[C:42](=[C:43]([CH3:45])[CH:44]=3)[N:41]=[CH:40][C:39]([C:46]([NH2:48])=[O:47])=[C:38]4[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=3)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:19][CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].NC[C@@H]([C:81]1[C:86]2[O:87][CH2:88][C:89](=[O:91])[NH:90][C:85]=2[CH:84]=[C:83]([OH:92])[CH:82]=1)O[Si](C(C)(C)C)(C)C>>[Si:1]([O:8][C@H:9]([C:81]1[C:86]2[O:87][CH2:88][C:89](=[O:91])[NH:90][C:85]=2[CH:84]=[C:83]([OH:92])[CH:82]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[CH:27]=[C:28]([S:32]([C:35]3[CH:36]=[C:37]4[C:42](=[C:43]([CH3:45])[CH:44]=3)[N:41]=[CH:40][C:39]([C:46]([NH2:48])=[O:47])=[C:38]4[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=3)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:21][CH:22]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1cc(O)cc2c1OCC(=O)N2
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6cc(O)cc7c6OCC(=O)N7)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 153, using (R)-8-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one in place of Intermediate 2. ES/MS calcd. for C52H57N6O9SSi+ 969.4. Found m/z=969.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].[CH3:23][N:24]1[CH:28]([CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][N:26]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[C:25]1=[O:53].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:49]([F:52])([F:51])[F:50])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:30][CH2:29][CH:28]2[CH2:27][N:26]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[C:25](=[O:53])[N:24]2[CH3:23])[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: CCOC(=O)C(C)(Cc1cccc(O)c1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1cccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)c1)Oc1ccc(C(F)(F)F)cc1
Temperature: 65 °C
Yield: 116.2 %

Procedure:
A mixture of 3-(3-hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.100 g, 0.271 mmol), toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (0.136 g, 0.298 mmol) and Cs2CO3 (0.133 g, 0.408 mmol) in DMF (8 mL) was heated to 65° C. under N2 for 17 h. The reaction was cooled and quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 4:1 hexanes:acetone to afford 0.113 g (64%) 2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester. 1H NMR. MS (ES+) Calc'd for C33H35N2O5F6 (M +1) 653. Found m/z 653 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccsc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 78.3 %

Procedure:
9.0 g of ethyl 3-(4-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate, 50 ml of dimethylformamide and 5.3 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 6.7 g of ethyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C@@H:11]3[CH2:13][C@H:12]3[CH:14]=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[OH:16][NH2:17]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C@@H:11]3[CH2:13][C@H:12]3[CH:14]=[N:17][OH:16])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C[C@@H]1C[C@H]1c1cccc2c1OCCO2
Reactant: NO
Product: ON=C[C@@H]1C[C@H]1c1cccc2c1OCCO2

Procedure:
(-)-(trans)-2-(2,3-Dihydro-1,4-benzodioxin-5-yl)-1-cyclopropanecarboxaldehyde was reacted with hydroxyl amine as described above to give the oxime as a mixture of isomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][C:13](=[O:15])[CH:12]=[CH:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([Li])CCC.[Br:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[CH2:32][C:33](Cl)=[O:34].[Cl-].[NH4+]>C1COCC1>[Br:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[CH2:32][C:33]([N:10]1[CH:11]=[CH:12][C:13](=[O:15])[CH2:14][CH:9]1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])=[O:34]
Reactant: COc1cc(Br)c(CC(=O)Cl)cc1OC
Reactant: N#Cc1cccc(C2CC(=O)C=CN2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(CC(=O)N2C=CC(=O)CC2c2cccc(C#N)c2)cc1OC
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
To 75 mg of 2-(3-cyanophenyl)-2,3-dihydro-pyridin-4-one in 8 ml THF at −75° C. was added 0.2 ml 2.5M n-butyl lithium. The mixture is stirred under argon at −75° C. for 10 minutes and then 106 mg 2-(2-bromo-4,5-dimethoxy-phenyl)acetyl chloride in 2 ml THF was added slowly. The reaction mixture was then stirred at −75° C. for 30 minutes, then allowed to warm to room temperature and was stirred for an additional 30 minutes. To this mixture was added 10 ml saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography of the residue gave 45 mg 3-{1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl}-benzonitrile. MS (M+H) 457.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:30])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:38]1([CH2:41][NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:40][CH2:39]1>C(O)C>[CH:43]1([N:42]([CH2:41][CH:38]2[CH2:39][CH2:40]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:30])=[O:9])[CH:3]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: C1CCC(NCC2CC2)CC1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 160 °C

Procedure:
A solution of tert-butyl 3-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate (Intermediate 34, 140 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (56.6 mg, 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent reduced to one tenth of the volume in vacuo. The solid formed was triturated with water and the residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate which was used directly without any further purification. The residue was redissolved in DCM (4.5 ml) and treated with TFA (0.5 ml). After stirring at RT for 2 hours the solvent was removed in vacuo to give the title compound as an off-white solid.
Reaction SMILES: C(O[CH:5]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16](OC(=O)C)[CH:15]2[CH:6]1[C:7](=[O:36])[C:8]1[C:9]3([S:35][CH2:34][CH2:33][S:32]3)[CH2:10][CH:11]([C:28]([O:30][CH3:31])=[O:29])[CH2:12][C:13]=1[C:14]2=[O:27])(=O)C.[OH-].[Na+]>CO.O>[O:36]=[C:7]1[C:6]2[C:15](=[CH:16][C:17]3[C:22]([CH:5]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:27])[C:13]2[CH2:12][CH:11]([C:28]([O:30][CH3:31])=[O:29])[CH2:10][C:9]3([S:32][CH2:33][CH2:34][S:35]3)[C:8]1=2
Reactant: COC(=O)C1CC2=C(C(=O)C3C(OC(C)=O)c4ccccc4C(OC(C)=O)C3C2=O)C2(C1)SCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)SCCS2
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
A mixture of 26.5 mg (0.05 mmol) of methyl rac-1',2',3',4',5',5a',6',11',11a',12'-decahydro-6',11'-diacetoxy-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate and 5 mg (0.125 mmol) of sodium hydroxide in 2 ml of methanol was stirred at 20° C. for 1.5 hours. The mixture was then diluted with 10 ml of water and extracted with two 10 ml portions of dichloromethane. The combined dichloromethane extracts were washed with 10 ml of water, dried over magnesium sulphate and evaporated to dryness to give 15 mg (73%) of methyl rac-1',2',3',4',5',12'-hexahydro-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate in the form of a bright yellow solid of melting point 216° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CS([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=1)(=O)=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)nc1
Yield: 55 %

Procedure:
To 18.4 g of 4-bromophenol dissolved in a 80 ml THF/80 ml DMSO mixture was added 13.1 g of t-BuOK and then 25.0 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled overnight and then poured into 3 volumes of water and stirred. The pink-white crystalline product was filtered, dissolved in CH2Cl2 and dried over MgSO4. Recrystallization from ethanol gave purified 2-(4-bromophenoxy)-5-(methylsulfonyl)pyridine, (55% yield), as white shiny needles, m.p. 125°-126° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]1[N:2]([CH3:1])[C:3]2[C:4]([N:13]=1)=[N:5][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:7][CH:8]=2)[CH3:15]
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1ccc(C(F)(F)F)nc1N
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2nc(C(F)(F)F)ccc2n1C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of N3-methyl-6-trifluoromethylpyridin-2,3-diamine (0.38 g), 2-ethylsulfanylbenzoic acid (0.40 g), WSC (0.42 g), and pyridine (3 ml) was stirred under reflux for hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. To the resulting residue, tripotassium phosphate (1.06 g) and 1-propanol (4 ml) were added, and stirred under reflux for 4 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of 2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 166).
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:3]([NH:6][C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([CH3:5])[CH3:4].O1CCCC1.[ClH:33]>O>[ClH:33].[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][NH:6][C:3]([CH:2]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[OH:1])([CH3:5])[CH3:4])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1cccc(C(O)C(C)(C)NC(=O)Cc2ccc(OC)c(OC)c2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(O)C(C)(C)NCCc2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 45 g. (0.12 mole) of N-(β-hydroxy-3-methoxy-α,α-dimethylphenethyl)-3,4-dimethoxybenzeneacetamide in 500 ml. dry tetrahydrofuran is added 200 ml. 1 M (0.2 mole) of BH3 /THF solution over 30 minutes at 0° C. with stirring. After addition, the reaction is allowed to stir overnight at room temperature. Water is added dropwise with caution until effervescence ceases, then 50 ml. more water is added all at once. Aqueous HCl (10%) is added to pH 1.0. Then the acidic reaction mixture is heated at 65° C. for 1 hour to remove most of the tetrahydrofuran and destroy excess BH3. Next, the mixture is cooled with ice and basicified with NH4OH. The mixture is extracted twice with 1 l. ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated to dryness in vacuo. The crude hydrochloride is made by dissolving the residue in 250 ml. ethyl acetate and adding a solution of ethyl acetate saturated with dry HCl to pH 2.0. On standing, 25 g. of crude solid is obtained, which is recrystallized from 300 ml. hot isopropanol to give 18.5 g. (39% yield) of α-(1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-1-methylethyl)-3-methoxybenzenemethanol hydrochloride as a white crystalline solid of analytical purity; m.p. 185°-186° C.