Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.CCCCCCC.CCOC(C)=O>[Pd].C(O)C>[CH2:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCC=C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCNCC1
Yield: 33 %

Procedure:
In a 500 mL flask fitted with a stirrer was added a slurry of 2 (13.2 g, 58 mmol) and 10% palladium on charcoal (1.2 g) in ethanol (70 mL), followed by addition of concentrated hydrochloric acid (1.5 mL). The reaction flask was evacuated and hydrogen was added via a reaction flask. A total of 2.5 dm3 of hydrogen was consumed. The reaction mixture was filtered and evaporated and the residue was dissolved in H2O (40 mL) and NaOH (20 mL, 2 M) followed by extraction with ethyl acetate (3×100 mL). The combined organic phases were washed with brine (30 mL) and evaporated to dryness to produce 7.1 g of crude 3. The crude product was subjected to CC [eluent:heptane:EtOAc (4:1)] to give pure 3 (2.7 g, 33%). 1H NMR (CDCl3) δ 0.85 (t, 3H), 1.0-1.38 (m, 9H), 1.65 (dd, 2H), 2.38 (s, 1H), 2.55 (dt, 2H), 3.04 (dt, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][CH2:11][C:10]1=[O:27].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][C:10]1=[O:27]
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC(=O)N(C)c2ccc(Cl)cc2C1c1ccccc1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
2.8 ml. (0.02 moles) of triethylamine are added to a solution of 5.73 g. (0.02 moles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 30 ml. of chloroform, and a solution of 2 ml. of ethyl chloroformate in 10 ml. of chloroform is added to the stirred mixture at room temperature. After 3 hours of stirring 1.4 ml. (0.01 moles) of triethylamine and a solution of 1 ml. of ethyl chloroformate in 5 ml. of chloroform are added to the reaction mixture. The reaction mixture is stirred for an additional 2 hours and then evaporated to dryness under reduced pressure. The residue is crystallized from ethanol. 6.7 g. (92.5%) of crystalline 1-methyl-4-ethoxycarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 173°-174° C., Rf1 = 0.5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:7][CH2:6]1.C(N(CC)CC)C.O1C[CH2:29][CH2:28][CH2:27]1.C(Cl)(=O)C=C>O>[CH:27]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:9][CH2:10]1)=[CH:28][CH3:29]
Reactant: OCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC=COCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 9.3 g of 1-[trans-4-(3-hydroxypropyl)cyclohexyl]-2,3-difluorobenzene, 4.1 g of triethylamine, and 100 ml of dry tetrahydrofuran were placed in a 200 ml flask. Then, 3.6 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=2/3) and recrystallized from hexane to obtain 6 g of 1-[trans-4-(3-propenyloxypropyl)cyclohexyl]-2,3-difluorobenzene (Y: 53%). The compound thus obtained had a purity of 99.8% by GC, 100% by HPLC, and of 1 spot by TLC. Furthermore, the compound had an m.p. of 35.5° C. to 36.9° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:24][C:22]1[CH:21]=[CH:20][C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)[CH:26]=[CH:25][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Reactant: CN1CCNCC1
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NC2COc4cc(F)ccc42)=N3)CC1
Yield: 99.2 %

Procedure:
Prepared from rac-2-chloro-N-[2-(6-fluoro-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 42 step A) (50 mg, 0.133 mmol, HPLC 1.056 min) and 1-methylpiperazine (300 ul, 2.66 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (58 mg, 99%, HPLC 0.468 min 100%), MS (ISP) m/e=440.3 [(M+H)+].
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9](O)=O.O=S(Cl)Cl.[NH3:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][NH2:16]
Reactant: N
Reactant: O=C(O)CC1CC2CCC1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=S(Cl)Cl
Product: NCCC1CC2CCC1C2
Yield: 35 %

Procedure:
Norbornane-2-acetic acid was treated with SOCl2, then with NH3. The resulting amine was reduced with LiAlH4 to give the desired intermediate. Yield: 35%.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:19][C@@H:20]([C@H:46]([OH:48])[CH3:47])[CH2:21][O:22][C:23]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:61]([N:64]([CH:78]([CH3:80])[CH3:79])[P:65](N(C(C)C)C(C)C)[O:66][CH2:67][CH2:68][C:69]#[N:70])([CH3:63])[CH3:62]>ClCCl>[CH:78]([N:64]([CH:61]([CH3:63])[CH3:62])[P:65]([O:66][CH2:67][CH2:68][C:69]#[N:70])[O:48][C@H:46]([CH3:47])[C@H:20]([CH2:19][N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][CH:17]=[N:18][C:10]=2[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][O:22][C:23]([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:80])[CH3:79]
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: COc1ccc(C(OC[C@@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 20 h
Yield: 93.1 %

Procedure:
To a stirred solution of 14 (0.9 g, 1.4 mmol) in 20 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.25 g) followed by 0.5 g (1.66 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. In about 5 hrs another 0.04 g of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite was added. The reaction was allowed to proceed for total 20 hrs and then concentrated. The resultant semi-solid was portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was precipitated twice by re-dissolving in small (˜5-10 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing to settle as an oil and decanting the liquid. Drying in vacuo afforded 1.1 g (93%) of 15 as a white amorphous solid. 31P NMR (DMSO-d6): δ 147.11, 146.16.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2cccnc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3cccnc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Quinoline-8-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1cccc(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1cccc(Cl)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
2.34 g of 5-(3-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.39 g of 3-chloro-5-(3-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xx) of the present invention).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([S:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:10]=[C:11]([CH:13]=O)[CH:12]=1.CO.[CH3:28][NH2:29].[BH4-].[Na+].[ClH:32].C(=O)([O-])O.[Na+]>CO>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([S:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:10]=[C:11]([CH2:13][NH:29][CH3:28])[CH:12]=1
Reactant: N#Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2F)cc1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(C#N)cc2)c1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
4-{[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile (385 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (844 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (124 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (50 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was purified with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3), and dissolved in methanol (10 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 274 mg, 62%).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14]2)[C@H:10]([CH2:24][OH:25])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:20]([O:19][C:17]([NH:16][C:13]1([C@H:11]2[CH2:12][NH:8][CH2:9][C@H:10]2[CH2:24][OH:25])[CH2:14][CH2:15]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2CO)CC1
Yield: 95 %

Procedure:
cis-1-Benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-hydroxymethylpyrrolidine (820.1 mg, 2.376 mmol) was dissolved in methanol (50 ml). After adding a 5% palladium-carbon catalyst (moisture content: 55.6%, 750 mg), the mixture was stirred under-elevated hydrogen pressure (4.5 kg/cm2) over a period of one day and night. After filtering off the catalyst through celite (washed with methanol), the filtrate was concentrat ed under reduced pressure to obtain 578.8 mg (91.0%) of the title compound as a white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[N:12]=[C:11]([C:22]([O:24]CC)=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[N:12]=[C:11]([C:22]([OH:24])=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(C#N)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: N#Cc1cccc(-n2nc(C(=O)O)cc2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 59A in analogy to the synthesis of the compound of Example 71A. 21 mg of the title compound with 83% purity (64% of theory) are obtained.
Reaction SMILES: [C:1]([S-:3])#N.[K+].[C:5]([NH:12][C@H:13]([C:17]([N:19]1[CH2:24][CH2:23]C=[CH:21][CH2:20]1)=[O:18])[CH:14]([CH3:16])[CH3:15])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>O.CCO>[S:3]1[CH:1]2[CH:21]1[CH2:20][N:19]([C:17](=[O:18])[C@@H:13]([CH:14]([CH3:15])[CH3:16])[NH:12][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:24][CH2:23]2
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CCC1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC2SC2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2.91 g of KSCN in 3 ml of H2O are added to a mixture of 5.96 g of 3,4-epoxy-N—(N-BOC-valyl-1,2,5,6-tetrahydropyridine in 10 ml of absolute EtOH and the mixture obtained is stirred for 72 hours at RT. The mixture obtained is subjected to aqueous extraction, the solvent of the organic phase obtained is evaporated and the evaporation residue is subjeted to chromatography. 3,4-Epithio-N(N-BOC-(R)-valyl)-piperidine is obtained. Melting point: 69.71°
Reaction SMILES: FC(F)(F)S(OC1CC[C@@H](N2C(C3C=CC=CC=3)C(C)(C)OC2=O)CC=1)(=O)=O.FC(F)(F)S(OC1CC[C@H](N2C(C3C=CC=CC=3)C(C)(C)OC2=O)CC=1)(=O)=O.FC1C(C2N=CC=CN=2)=CC(B2OC(C)(C)C(C)(C)O2)=CN=1.C(=O)([O-])[O-].[Na+].[Na+].[F:85][C:86]1[N:91]=[CH:90][C:89]([C:92]2[CH2:97][CH2:96][C@H:95]([N:98]3[CH:102]([C:103]4[CH:108]=[CH:107][CH:106]=[CH:105][CH:104]=4)[C:101]([CH3:110])([CH3:109])[O:100][C:99]3=[O:111])[CH2:94][CH:93]=2)=[CH:88][C:87]=1[C:112]1[N:117]=[CH:116][CH:115]=[CH:114][N:113]=1>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.O1CCOCC1>[F:85][C:86]1[N:91]=[CH:90][C:89]([C:92]2[CH2:97][CH2:96][C@@H:95]([N:98]3[CH:102]([C:103]4[CH:108]=[CH:107][CH:106]=[CH:105][CH:104]=4)[C:101]([CH3:110])([CH3:109])[O:100][C:99]3=[O:111])[CH2:94][CH:93]=2)=[CH:88][C:87]=1[C:112]1[N:113]=[CH:114][CH:115]=[CH:116][N:117]=1
Reactant: CC1(C)OC(=O)N([C@@H]2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cnc(F)c(-c3ncccn3)c2)OC1(C)C
Agent: CC1(C)OC(=O)N([C@@H]2CC=C(OS(=O)(=O)C(F)(F)F)CC2)C1c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N([C@H]2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)C1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A microwave vial was charged with a mixture of (4R)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohex-1-en-1-yl trifluoromethanesulfonate and (4S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohex-1-en-1-yl trifluoromethanesulfonate (Intermediate M) (730 mg, 1.741 mmol), 2-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)pyrimidine (Intermediate H) (577 mg, 1.915 mmol), sodium carbonate (2 M, 2.611 mL, 5.22 mmol), and tetrakis(triphenylphosphine)palladium(0) (201 mg, 0.174 mmol) (commercially available from Strem Chemicals Inc., Newburyport, Mass.). Dioxane (8.703 mL) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. in the microwave for 1 hour. LC-MS indicated clean and good conversion to the desired product. The reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford a yellow oil. The oil was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0 to 60% EtOAc-heptane) to afford a mixture of 3-((S)-4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one and 3-((R)-4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (370 mg, 0.832 mmol, 47.8% yield) as a white solid. m/z (ESI) 445.2 (M+H)+.
Reaction SMILES: [OH-].[K+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.O>CS(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])=[N:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(Cl)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
9.9 g potassium hydroxide powder and 5.0 g 1-fluoro-2-nitrobenzene were added little by little in this order to a solution of 5.8 g 5-chloro-2-aminopyridine in dimethyl sulfoxide (100 mL), and the mixture was stirred at 20° C. for 4 hours under nitrogen atmosphere. The reaction solution was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane, to give 6.02 g of the title compound as orange crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:3]1OC.C[Si]([C:24]#[N:25])(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[C:24]([CH:3]1[C:2]([CH3:19])([CH3:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])#[N:25]
Reactant: COC1N(C(=O)OCc2ccccc2)CCC1(C)C
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CCN(C(=O)OCc2ccccc2)C1C#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
In a 500 ml flask was dissolved phenylmethyl 3,3-dimethyl-2-(methyloxy)-1-pyrrolidinecarboxylate (0.0426 mol, 11.2 g) in 200 ml methylene chloride under argon. After the solution was cooled to −78° C., trimethylsilyl cyanide (0.0640 mol, 6.32 g) was added followed by boron triflouride etherate (0.0640 mol, 9.09 g). After 1 hr of stirring, the reaction was quenched with saturated aqueous sodium bicarbonate and allowed to warm to 20° C. After 2 hr of vigorous stirring, the aqueous phase was separated and extracted with methylene chloride (2×100 ml). All organics were combined, dried over MgSO4, filtered and concentrated yielding 10.8 g (98%) of phenylmethyl 2-cyano-3,3-dimethyl-1-pyrrolidinecarboxylate as a clear oil which was used without further purification. LCMS (ESI+)=259 m/z (MH+). 1H NMR (400 MHz, CDCl3)— rotamers δ 7.44-7.35 (m, 5H), 5.21 and 5.20 (s, 2H), 4.26 and 4.17 (s, 1H), 3.64-3.51 (m, 2H), 2.01-1.95 (m, 1H), 1.80-1.74 (m, 1H), 1.36 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: O[C:2]1([CH:17]=[CH2:18])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.S(Cl)([Cl:21])=O.O>ClCCl>[Cl:21][CH2:18][CH:17]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: C=CC1(O)c2ccccc2C=Cc2ccccc21
Solvent: O
Solvent: ClCCl
Product: ClCC=C1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of 5-hydroxy-5-vinyl-5H-dibenzo[a,d]cycloheptene (11 g, 48 mmol) in dichloromethane (300 ml) at 0° C. under argon atmosphere is added dropwise thionylchloride (62 mmol, 4.6 ml). The mixture is then stirred for 4 hours at room temperature. Water (100 ml) is added, the organic phase is removed and the aqueous phase is extracted with ether (350 ml). The combined organic phases are washed with water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is taken up in 150 ml of hot isooctane, the insoluble material is removed by decantation and the solution is cooled to room temperature, whereby the expected product crystallizes. The crystalline material is filtered, washed with isooctane and dried: 9 g of the pure title compound is obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[S:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:25][N:26]=1>>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:21][C:22]2[S:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:25][N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(c2cnc(N)s2)CC1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Product: CN1CCN(c2cnc(NC(=O)C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)s2)CC1

Procedure:
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-propionamide was prepared from 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and 2-amino-5-(4-methyl-piperazin-1-yl)thiazole as described in Example 1. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.68 (d, 2H), 6.80 (s, 1H), 3.95 (t, 1H), 3.57 (m, 4H), 3.29 (m, 2H), 3.16 (m, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 2.22-2.15 (m, 1H), 1.88-1.43 (m, 8H), 1.21-1.11 (m, 2H); HPLC-MS: m/z=477 (M+1).