Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[OH:12].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([S:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:22][CH:21]=2)[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1O
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
A mixture of 2-methyl-4-nitro-5-chloro phenol (1.5 g, 8.0 mmol), 4-Acetamido thiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6 mmol) in DMF (10 mL) was heated 2.5 h at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer was washed with water and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent removed under vacuum leaving N-[4-(5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide as a solid (2.5 g, 81%). A solution of N-[4-(5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide (2.5 g, 6.45 mmol), iron powder (1.79 g, 32 mmol) and ammonium chloride (0.514 g, 9.6 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide N-[4-(2-Amino-5-hydroxy-4-methyl-phenylsulfanyl)-phenyl]-acetamide (1.7 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13]O)[CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>C(Cl)Cl>[Cl:35][CH2:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:12][N:11]=1
Reactant: OCc1cc(-c2ccc(F)cc2)on1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2cc(CCl)no2)cc1
Temperature: 65 °C

Procedure:
To a solution of [5-(4-fluorophenyl)-3-isoxazolyl]methanol (0.2 g, 1.04 mmol) in 5 mL of CCl4 and 0.5 mL of CH2Cl2 was added Ps-triphenylphosphine (3 mmol/g, 0.69 g, 2.08 mmol), and the mixture was heated at 65° C. for 3 h. Upon cooling, the resin was filtered off and washed with CH2Cl2 and EtOAc. The filtrate was concentrated to dryness to afford the title compound as a light brown solid, which was used in the next reaction without further purification: 1H NMR (400 MHz, CDCl3) δ 7.75 (t, J=6.6 Hz, 2H), 7.14 (t, J=8.3 Hz, 2H), 6.55 (s, 1H), 4.6 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=3)[CH2:8][CH2:9][O:10][C:11]=2[N:12]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.CN(C)C(=O)C>>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)=[N:12][C:11]=4[O:10][CH2:9][CH2:8][N:7]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Cl)nc1OCC2
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(C)CC3)nc1OCC2

Procedure:
A solution of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine (66.0 mg, 0.200 mmol), 1-methyl-piperazine, (88.5 uL, 0.798 mmol) and Triethylamine (167 uL, 1.20 mmol) in N,N-Dimethylacetamide (3.00 mL, 32.3 mmol) was heated in microwave at 16° C. for 20 min. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water, brine. The organic layer was dried Na2SO4, concentrated. The crude product was purified by rHPLC to give 323. MS: (ESI+)=395.2. 1H NMR (400 MHz, DMSO) δ 8.50 (d, J=8.7 Hz, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 6.72 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.7 Hz, 1H), 4.49 (m, 4H), 3.61-3.48 (m, 4H), 2.42-2.34 (m, 4H), 2.21 (s, 3H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[C:24]([CH3:26])[CH:25]=1)=[O:18].C[C:34]1N(C2C=CC(C(F)(F)F)=CN=2)N=[CH:36][C:35]=1[C:49](NC1C=NC(C2CCNCC2)=C(C)C=1)=[O:50]>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([C:27]2[CH2:28][CH2:29][N:30]([C:49](=[O:50])[CH:35]([CH3:36])[CH3:34])[CH2:31][CH:32]=2)=[C:24]([CH3:26])[CH:25]=1)=[O:18]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)C(C)C)CC1

Procedure:
5-Methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide described in Reference Example 170 in place of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)-pyridin-2-yl]-1H-pyrazole-4-carboxamide in Example K61, and reacted and treated in a similar manner to give the titled compound as a pale yellow solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[C:31](C#N)=[CH:30][CH:29]=[CH:28][C:27]=2C#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:36][OH:37].Cl.[CH3:39][OH:40].O>C1(C)C=CC=CC=1>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[C:27]([CH:36]=[O:37])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:39]=[O:40])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO
Reactant: N#Cc1cccc(C#N)c1CCCCCCCCCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(C=O)c1CCCCCCCCCc1ccccc1

Procedure:
A solution of diisobutylaluminium hydride in toluene (3.1 ml, 4.6 mmol) was added dropwise to a stirred solution of 2-(9-phenylnonyl)-1,3-benzenedicarbonitrile (0.70 g, 2.1 mmol) in dry toluene (30 ml) under nitrogen, cooled in an ice bath. After one hour at room temperature methanol (1 ml) was added cautiously, followed by methanol:water (1:1, 1 ml) and 5M hydrochloric acid (15 ml). The mixture was extracted with diethyl ether (20 ml) and the extracts dried, filtered and evaporated to a yellow oil (0.8 g). Chromatography on flash silica eluting with dichloromethane gave 2-(9-phenylnonyl)-1,3benzenedicarboxaldehyde as a colourless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.7 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3 g (67%); white solid; mp 182° C.; MS: 446 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1>>[OH:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:25])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:26])[CH:32]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCO)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.928 min, m/z=444.4; 1H NMR (CDCl3) 1.50 (d, 3H), 2.05-2.18 (m, 2H), 2.26-2.39 (m, 6H), 2.82 (s, 3H), 2.94 (m, 1H), 3.51 (m, 1H), 3.72 (m, 1H), 5.54 (m, 1H), 7.00 (d, 2H), 7.24-7.38 (m, 7H), 7.57 (s, 1H), 7.64 (d, 1H), 8.75 (d, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+]>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:7]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NS(=O)(=O)c3ccccc3)c2)CC1
Reaction time: 0.03 h
Yield: 78 %

Procedure:
N-(5-fluoro-2-nitrophenyl)benzenesulfonamide (2×0.50 g, 1.688 mmol) was treated with N-methyl-piperazine (2×4.65 g, 45.6 mmol) and put in two pyrex tubes and sealed. Each tube was put in a LabWell MW-10 microwave oven for 2 min at 50 W. The reaction mixtures were combined and poured into 0.5 M NaOH (aq) and extracted with CH2Cl2, dried (MgSO4) and concentrated to give 0.99 g, (2.63 mmol) in 78% yield as a yellow solid. Anal (C17H20O N4 O4 S)C, H, N, S; MS (posES-FIA) m/z=found: 377.4; Calcd: 376.12.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH:13]=1)=[O:10])([CH3:4])[CH3:5])#[N:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cc1

Procedure:
Using 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methylphenyl)benzamide (1.47 g, 5.0 mmol), 1-fluoro-4-nitrobenzene (0.77 g, 5.5 mmol) and potassium carbonate (0.69 g, 5.0 mmol), and in the same manner as in Example A25(iii), the title compound (2.08 g, quantitatively) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])(C)C)=[O:10].[BH4-].[Na+].O.[C:19](OCC)(=O)[CH3:20]>CO>[OH:8][CH:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][CH2:12][CH2:15][CH2:19][CH3:20])=[O:10])[CH:2]([CH3:1])[CH2:7]1
Reactant: CCOC(C)=O
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCOC(=O)N1CCC(O)CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (0.94 g, 4.41 mmol) in methanol (5 mL) was added sodium borohydride (0.22 g, 5.73 mmol) and the reaction was stirred at room temperature for 1 h. Water was added slowly, followed by ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product as a mixture of four stereoisomers, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]([OH:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: NC(=S)c1ccc(F)cc1
Product: Oc1nc(-c2ccc(F)cc2)sc1-c1ccccc1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except 4-fluorothiobenzamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([OH:14])=[O:13]>C(Cl)Cl.CO>[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([O:14][CH3:1])=[O:13]
Reactant: Nc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C

Procedure:
(Trimethylsilyl)diazomethane (6 mL, 2M solution in hexanes) was added to a solution of 3-amino-4-nitro-benzoic acid in CH2Cl2 (25 mL) and methanol (25 mL). Stirred at room temperature until bubbling ceased. Concentrated under vacuum to provide 1.2 g of desired product. MS (DCI) m/e 197 (M+H)+.
Reaction SMILES: [CH2:1]([OH:5])[C@@H:2]([OH:4])[CH3:3].[H-].[Na+].[CH2:8]([N:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[S:14]/[C:13]/1=[N:21]\[C:22](=[O:34])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1F)[CH2:9][CH2:10][CH3:11]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:8]([N:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[S:14]/[C:13]/1=[N:21]\[C:22](=[O:34])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:5][CH2:1][C@@H:2]([OH:4])[CH3:3])[CH2:9][CH2:10][CH3:11]
Reactant: C[C@H](O)CO
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)O)sc2ccncc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.2 %

Procedure:
(S)-propane-1,2-diol (52 mg, 0.68 mmol) in THF (1 mL) was treated with NaH (60% dispersion; 27 mg, 0.68 mmol) at room temperature for 20 minutes. The mixture was cooled to 0° C. and a solution of Example 20B (90 mg, 0.23 mmol) in THF (1 mL) was added. The mixture was allowed to warm to room temperature, and stirred for 4 hours. The mixture was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 19 mg (19%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (t, J=7.48 Hz, 3H) 1.28 (d, J=6.41 Hz, 3H) 1.47-1.59 (m, 2H) 1.88-1.98 (m, 2H) 3.87 (t, J=8.85 Hz, 1H) 4.21-4.31 (m, 1H) 4.35 (dd, J=9.15, 2.75 Hz, 1H) 4.51-4.59 (m, 2H) 7.12 (d, J=8.85 Hz, 1H) 7.72 (dd, J=8.54, 2.14 Hz, 2H) 8.51 (d, J=1.83 Hz, 2H) 8.75 (s, 1H); MS (DCI/NH3) m/z 454 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]O)[CH:23]=1>>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:23]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1cccc(-c2c(F)cccc2F)c1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3c(F)cccc3F)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 277 from methyl 3-(4-hydroxyphenyl)propanoate and (2′,6′-difluorobiphenyl-3-yl)methanol. colorless oil (yield 60%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=2[O:20][CH3:21])[C:6](=[O:22])[CH2:5]1>C(O)C.O>[OH:22][C@H:6]1[C@@H:7]([C:10]2[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5]1
Reactant: COc1cc(OC)c(C2CCN(C)CC2=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c([C@H]2CCN(C)C[C@H]2O)c(OC)c1

Procedure:
Sodium borohydride (10 g) is added with stirring to a solution, boiling under reflux, of 1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidin-3-one in absolute ethanol. Stirring and heating under reflux is then continued for a further hour. On cooling, the reaction mixture is diluted with water, then concentrated in order to remove the ethanol and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and concentrated to give a solid residue which, on crystallization from acetone, gives the desired product (29.2 g) of melting point 124°-125° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH3:25][C@H:26]([NH2:29])[CH2:27][OH:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:29][C@@H:26]([CH3:25])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Product: C[C@@H](CO)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 59 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (60 mg, 0.18 mmol) was converted, using S-(+)-2-amino-1-propanol instead of rac-2-amino-1-propanol, to the title compound (28 mg, 59%) which was obtained as a white solid MS: m/e=370.3 [M−H]−.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:12]=[N:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][C:20]1[S:24][C:23]([NH2:25])=[N:22][CH:21]=1>>[Br:19][C:20]1[S:24][C:23]([NH:25][C:8](=[O:10])/[C:7](/[C:11]2[CH:12]=[N:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)=[CH:6]/[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:22][CH:21]=1
Reactant: Nc1ncc(Br)s1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)O)cn1
Product: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Br)s2)cn1

Procedure:
Condensation of (E)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylic acid (Preparation 3, 64 mg, 0.24 mmol) with 5-bromothiazol-2-ylamine (218 mg, 1.22 mmol), by the protocol described in EXAMPLE 5, yielded (E)-N-(5-bromothiazol-2-yl)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylamide: RTA=4.28 min; m/z (ES+)=426.2 [M+H]+. This compound (61 mg, 144 μmol) was oxidised, employing the procedure described in EXAMPLE 35, to give the title compound: RTA=3.91 min; m/z (ES+)=499.2 [M+MeCN+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([F:15])[CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([F:15])[CH:3]=1
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)Cc1cc(F)c(N)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1cc(F)c(CC(=O)O)cc1F
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a stirred solution of ethyl 4-amino-2,5-difluorophenylacetate (323 mg, 1.5 mmol) in DMF (8 mL), were added triethylamine (0.209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0.372 ml, 3.0 mmol) at rt. The stirring was continued for 48 hour at 80° C. The reaction mixture was evaporated in vacuo, and the solid was suspended to n-hexane. The solid was collected through filtration. The solid was dissolved in THF-MeOH (1:1, v/v, 20 mL), and was added 4M NaOH (10 mL) at rt. The stirring was continued for 18 hours at rt. The reaction was poured into 1M HCl, and the resulting precipitate was collected through filtration. The solid was recrystallized with CHCl3-n-hexane to give 4-[(2-methylphenyl)ureido]-2,5-difluorophenylacetic acid (214 mg, 46%) as a white solid. 1H-NMR (CDCl3) δ 2.30 (s, 3 H), 3.35 (m, 2 H), 7.02 (m, 2 H), 7.18 (d, J=7.3 Hz, 2 H), 7.69 (d, J=7.8 Hz, 1 H), 8.03 (m, 1 H); MS (FAB) m/z 321 (M++1).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][C:7](=O)[CH3:8])[CH3:2].[NH3:12]>>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][CH2:6][CH:7]([NH2:12])[CH3:8])[CH2:10][CH3:11]
Reactant: N
Reactant: CCN(CC)CCCC(C)=O
Product: CCN(CC)CCCC(C)N

Procedure:
Novoldiamine is presently prepared by a complex synthesis. The compound is prepared commercially from 2-diethylaminoethanol and ethyl acetoacetate. The alcohol is reacted with thionyl chloride to form 2-chlorotriethylamine (A) while the acetoacetate is reacted with sodium ethoxide to provide the sodium derivative of ethyl acetoacetate (B). The initially formed compounds A and B are then condensed to yield an intermediate ester which must be hydrolyzed and then decarboxylated to provide 5-diethylamino-2-pentanone (C). This product (C) is hydrogenated in the presence of ammonia to produce the subject novoldiamine product. Other modes of preparation are known (See U.S. Pat. No. 2,365,825), but are not practiced due to the complexity of the synthesis.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:13])[N:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1[OH:8].[CH2:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:13])[N:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[N:5]=[CH:6][C:7]=1[O:8][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:17][CH2:14][CH2:15][CH3:16])=[CH:29][CH:28]=1
Reactant: CCCOCCCOc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOCCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Br)cc1
Reaction time: 3 h
Yield: 41.7 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1.7 g of 4-bromo-2-t-butyl-5-hydroxy-3(2H)-pyridazinone and 2.0 g of 4-(3-propoxypropoxy)-benzyl bromide, and 1.3 g of anhydrous potassium carbonate was added thereto. The resulting mixture was heated under stirring on an oil bath at 80° to 90° C. for 3 hours. Then, procedures similar to those in Preparation Example 2 were carried out to obtain 1.3 g of the aimed compound as an oil.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH3:24])[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][N:14]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[N:27]1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:8][C:9]1[C:10]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[S:31]([C:29]3[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=3)(=[O:33])=[O:32])[CH2:19][CH2:20]2)=[N:11][CH:12]=[CH:13][N:14]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Add triethylamine (0.852 mL, 6.116 mmol) to a stirring solution of [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine (0.500 g, 1.529 mmol) in dichloromethane (10 mL). Add 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.331 g, 1.834 mmol) at room temperature. Stir at room temperature for 18 hr. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate and extract the aqueous layer with dichloromethane. Combine the organic layers, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 6:4 to 4:6 to afford the title preparation (0.514 g, 84% yield). MS ES: m/z=400 [M+H]+.