Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1>C(#N)C>[Cl:15][CH:2]([Cl:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]([NH:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1)=[O:14])(=[O:11])=[O:10]
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(Cl)Cl
Solvent: CC#N
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(Dichloromethyl)benzenesulfonyl isocyanate, prepared from 10 mmol of sulfonamide as described in the synthesis of Example 1, was treated with acetonitrile and 2-amino-4,6-dimethylpyrimidine (1.23 g). The mixture was stirred at room temperature for 18 hrs, cooled, and filtered to provide 1.08 g of white solid, mp 195°-197° (Dec). 1H nmr δCDCl3/DMSO-d6TMS 10.53 (s), 8.20-7.90 (m, featuring singlet at 8.00), 7.87-7.43 (m), 6.83 (s), 2.43 (s). IR (nujol) featured bands at 1710 and 1600 cm-1. Mass spectrum featured m/e 388.0174 (calc'd for C14H14Cl2N4O3S 388.0163); 150.0627 (calc'd for C7H7N3 150.0667).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5]([C:8]1[C:16]2[S:15][C:14]([NH:17][C:18](=[O:22])[NH:19][CH2:20][CH3:21])=[N:13][C:12]=2[CH:11]=[C:10]([C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH:9]=1)(=O)[CH3:6]>CN(C=O)C>[CH2:20]([NH:19][C:18]([NH:17][C:14]1[S:15][C:16]2[C:8](/[C:5](/[CH3:6])=[N:4]/[O:3][CH3:2])=[CH:9][C:10]([C:23]3[CH:28]=[N:27][C:26]([N:29]4[CH2:30][CH2:31][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34]4)=[N:25][CH:24]=3)=[CH:11][C:12]=2[N:13]=1)=[O:22])[CH3:21]
Reactant: CON
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(C)=O)c2s1
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(/C(C)=N/OC)c2s1
Temperature: 60 °C

Procedure:
O-Methyl hydroxylamine hydrochloride (64 mg, 0.784 mmol) was added to ethyl 1-[5-[7-acetyl-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (200 mg, 0.39 mmol) in DMF (5 mL). The reaction mixture was heated to 60° C. for 4 h after which time LCMS indicated clean conversion to the desired product. The reaction was diluted with EtOAc, washed with water then brine and the organic layer dried (MgSO4), filtered and the solvent removed in vacuo. The crude product obtained was used in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](OB(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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.O.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(OB(O)O)cc1
Reactant: N#Cc1cccc(Cl)n1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cccc(C#N)n2)cc1
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
6-Chloro-2-pyridinecarbonitrile (0.70 g, 5.0 mmol) and 4-methoxyphenylboric acid (1.17 g, 7.7 mmol) were dissolved in toluene (60 ml)-ethanol (15 ml), and potassium carbonate (1.75 g, 12.6 mmol) and water (15 ml) were added thereto. The mixture was deairated under reduced pressure for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.29 g, 0.25 mmol) was added to the reaction mixture under argon atmosphere, and the mixture was refluxed for 16 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.94 g, 88%).
Reaction SMILES: C1(C2NN=C(NC3C(=O)N(C)C=C(C4C=CN=C(N5CCN6C7CCCCC=7C=C6C5=O)C=4CO)C=3)C=2)CC1.C([O-])(=O)C.C([O:47][CH2:48][C:49]1[C:50]([N:81]2[CH2:93][CH2:92][N:84]3[C:85]4[CH2:86][CH2:87][CH2:88][CH2:89][C:90]=4[CH:91]=[C:83]3[C:82]2=[O:94])=[N:51][CH:52]=[CH:53][C:54]=1[C:55]1[CH:60]=[C:59]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([N:68]3[CH2:73][CH2:72][N:71]([CH2:74][C:75]([OH:78])([CH3:77])[CH3:76])[CH2:70][CH2:69]3)=[CH:64][N:63]=2)[C:58](=[O:79])[N:57]([CH3:80])[CH:56]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[OH:78][C:75]([CH3:77])([CH3:76])[CH2:74][N:71]1[CH2:72][CH2:73][N:68]([C:65]2[CH:66]=[CH:67][C:62]([NH:61][C:59]3[C:58](=[O:79])[N:57]([CH3:80])[CH:56]=[C:55]([C:54]4[CH:53]=[CH:52][N:51]=[C:50]([N:81]5[CH2:93][CH2:92][N:84]6[C:85]7[CH2:86][CH2:87][CH2:88][CH2:89][C:90]=7[CH:91]=[C:83]6[C:82]5=[O:94])[C:49]=4[CH2:48][OH:47])[CH:60]=3)=[N:63][CH:64]=2)[CH2:69][CH2:70]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(CC(C)(C)O)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC(=O)[O-]
Agent: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc(C3CC3)[nH]n2)c1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(CC(C)(C)O)CC3)cn2)c1=O
Yield: 41.4 %

Procedure:
Following the procedures as described for the preparation of 118, acetate hydrolysis of 120b (70 mg, 0.1 mmol) with LiOH.H2O in iPrOH/THF (1:1) and H2O, gave 120 (27 mg, 42%) as a gray solid. LCMS: [M+H] 653. 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=3, 1H), 8.50 (d, J=5, 1H), 8.41 (s, 1H), 7.83 (d, J=3, 1H), 7.46 (d, J=2, 1H), 7.36 (m, 2H), 7.24 (d, J=9, 1H), 6.58 (s, 1H), 4.95 (m, 1H), 4.44 (m, 2H), 4.24 (m, 2H), 4.13 (m, 2H), 3.87-3.88 (m, 1H), 3.60 (s, 3H), 3.03-3.05 (m, 4H), 2.64-2.66 (m, 5H), 2.61-2.63 (m, 1H), 2.49-2.51 (m, 2H), 2.24 (s, 2H), 1.70-1.71 (m, 4H), 1.10 (s, 6H).
Reaction SMILES: [CH2:1]=[C:2]1O[C:4](=[O:5])[CH2:3]1.[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1>C(O)(=O)C>[CH3:15][C:14]1[O:16][C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:13]=1[C:10]1[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=1
Reactant: C=C1CC(=O)O1
Reactant: CC(=O)Cc1ccncc1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(-c2ccncc2)c(C)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.6 %

Procedure:
Diketene (30 g) was added dropwise to a stirred solution of 1-(4-pyridyl)-2-propanone (20.25 g) in acetic acid (100 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 90 minutes. The mixture was heated to 50° and stirred for a further 90 minutes. The solvent was removed by evaporation and the residue purified by flash chromatography, eluting with dichloromethane/methanol (19:1 v/v) to give 2,6-dimethyl-3-(4-pyridyl)-4H-pyran-4-one (C) (21.6 g), as a yellow solid; NMR (CDCl3): 2.28(s,3H), 2.35(s,3H), 6.2(s,1H), 7.2(dd,2H), 8.65(dd,2H); mass spectrum (chemical ionisation, ammonia): 202 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]2)[N:22]=1>CC(O)C.CS(C)=O>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH2:29][CH2:30][CH:31]([NH:34][CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=3)[CH2:32][CH2:33]2)[N:22]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3ccc(O)cc3)CC2)n1
Yield: 64 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 35 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 6:4:1) with 64% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 3:7:1.5) with 10% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[NH:20][C:21](=[O:25])[N:22]=[CH:23][CH:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:32][C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: ClCc1cccnc1
Reactant: N#Cc1cc(COc2ccnc(=O)[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: N#Cc1cc(COc2ccn(Cc3cccnc3)c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-2,3-dihydro-4-pyrimidinyl)oxy]methyl}benzonitrile and 3-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 513 [M+H]+; 2.94 min (ret time).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.[Mg].[B:19](OC)([O:22]C)[O:20]C.Cl>O1CCCC1>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[CH:3][C:4]=2[F:17])=[CH:9][CH:10]=1)[CH2:15][CH3:16]
Reactant: COB(OC)OC
Reactant: CCCc1ccc(-c2ccc(Br)cc2F)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(B(O)O)cc2F)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
The product from step (ii) (10 g; 0.034 mol) in tetrahydrofuran (35 ml) was added dropwise to a suspension of magnesium turnings (0.88 g) in tetrahydrofuran (5 ml). The mixture was warmed to 75° C. when the Grignard reaction started. Further of the bromo compound was slowly added and the external heat source removed, a gentle reflux being maintained. After complete addition, the mixture was heated for 30 mins under reflux and then cooled to 15° C. A dry nitrogen atmosphere was introduced and trimethyl borate (3.77 g; 0.0363 mol) was slowly added and the mixture stirred at 15°-20° C. for 16 hrs. A 20% soln of hydrochloric acid (50 ml) was slowly added, the organic layer was separated, and the aqueous layer extracted with ether (2×50 ml). The combined organic layers were washed with brine and dried over sodium sulphate. Upon evaporation of the solvents a yellow solid was obtained. Yield 8.7 g; 100%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10](Br)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36].O>O1CCCC1.CCCCCC>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:35]=[O:36])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Br)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C=O)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 810 mg (1.9 mmol) of 1-benzyl-3-bromo-7-(4-fluorobenzyloxy)-2-methylpyrrolo[2,3-d]pyridazine in 30 ml of anhydrous tetrahydrofuran is cooled to -70° C. under argon and treated with 1.65 ml (2.7 mmol) of a 15% strength solution of n-butyllithium in hexane. The mixture is subsequently stirred at -70° C. for a further 30 min. After addition of 215 μl (2.7 mmol) of anhydrous dimethylformamide, the temperature is kept at -70° C. for a further 30 min and subsequently slowly increased to 20° C. The solution is then treated with 100 ml of water and extracted with 3×50 ml of ethyl acetate. The organic extracts are washed with 50 ml of water, dried over magnesium sulfate and concentrated. The residue which remains is chromatographed on silica gel (eluent: ethyl acetate). After concentration of the fractions of Rf=0.4 and crystallization from diisopropyl ether, 150 mg (21%) of the title compound are isolated. M.p.: 136°-141° C.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].CC([Si](C)(C)[O:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)(C)C>>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:33]2[CH2:34][CH2:35][C@H:31]([OH:30])[CH2:32]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1
Reactant: Cc1nc(C(C)(C)NC(=O)c2ccc(Br)c(OCC3CC3)n2)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CC[C@H](O)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 322b, using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 322a) and (35)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-pyrrolidine (CAN 207113-36-8) as starting materials. The protecting group was removed with tetrabutylammonium fluoride in THF; LC-MS (UV peak area/ESI) 100%, 402.2134 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:16])[CH2:14][OH:15])[CH:7]=[CH:6]2.I([O-])(=O)(=O)=[O:18].[Na+]>C(Cl)(Cl)(Cl)Cl.C(#N)C.O.O.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:16])[C:14]([OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc2cc(C(C)CO)ccc2c1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
To a solution of 0.21 g 2-(6-methoxy-2-naphthyl)propan-1-ol in 2 ml of carbon tetrachloride, 2 ml acetonitrile, 3 ml of water, and 0.877 g of sodium metaperiodate is added 5 mg of ruthenium trichloride hydrate. After 4 hours at ambient temperature the mixture is extracted with 4 portions of 10 ml of methylene chloride. The combined organic extracts are dried over MgSO4, filtered, and concentrated to give the product 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]1[CH2:24][O:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[C@@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][NH:28][CH2:27]1>C(O)C>[OH:23][C@H:22]([CH2:21][O:20][C:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:24][N:28]1[CH2:29][CH2:30][C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])[C@@H:26]([CH3:25])[CH2:27]1
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Reactant: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: C[C@H]1CN(C[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
(S)-2-Trityloxymethyl-oxirane (636 mg, 2 mmol) and 2,2-dimethyl-propionic acid (3S,4S)-3-methyl-piperidin-4-yl ester (17, 400 mg, 2 mmol) are dissolved in 7 ml of ethanol and stirred at room temperature for 23 h. The white suspension is heated to 40° C. and stirred for additional 2 h. The reaction mixture is evaporated under reduced pressure and the crude product is purified by Flash-chromatography. (silica gel, 20% ethyl acetate in cyclohexane).
Reaction SMILES: [CH3:1][C:2]([CH:7]([CH3:9])[CH3:8])=[CH:3][C:4](Cl)=[O:5].C[CH:11](C)[C:12](=[O:14])C.[H-].[Na+]>COCCOCCOC>[CH3:1][C:2]([CH:7]([CH3:9])[CH3:8])=[CH:3][C:4]([O:14][CH2:12][CH3:11])=[O:5]
Reactant: CC(=CC(=O)Cl)C(C)C
Reactant: CC(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)C=C(C)C(C)C

Procedure:
The 3,4-dimethyl-2-pentenoyl chloride (IX) utilized in the procedures of the present invention may be readily prepared from 3-methyl-2-butanone (XII) utilizing the Wittig reaction. In this procedure triethylphosphonoacetate is added to a suspension of sodium hydride in diglyme in an inert atmosphere at a temperature of between -10° C. and 5° C., suitably about 0° C. The mixture is stirred, suitably for about half an hour, to ensure formation of the Wittig reagent and the ketone (XII) added slowly thereto. There is utilized approximately 100% molar excess of the triethylphosphonoacetate with respect to the ketone (XII). The reaction is completed by allowing the reaction mixture to equilibrate with room temperature after completion of the addition, and remaining at ambient temperature from between 2 to 5 hours. The mixture is then recooled and carefully quenched with a large excess of water and the reaction product extracted therefrom with a reaction inert water insoluble organic solvent, suitably ether and the thus produced ethyl 3,4-dimethyl-2-pentenoate (XI) isolated from the ethereal extract in the usual manner.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.035 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.9 Hz, 1H), 7.84 (d, J=6.5 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.50 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.68 (t, J=7.3 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.7 Hz, 1H), 5.19 9t, J=6.1 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 3.20-3.14 (m, 7H), 2.69-2.58 (m, 4H), 2.39 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:31])[C:19]([CH3:30])([S:21]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(O)C>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:31])[C:19]([CH3:30])([S:21]([CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH3:1]
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Yield: 82.7 %

Procedure:
A solution of 98 g (0.21 mol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide in DCM/ethanol (1/1, 1.2 L) is treated with 129 g (0.42 mol) of MP-TsOH resin (loading 3.3 mmol/g) at room temperature for 18 h. The resin is removed by filtration and washed alternating with DCM (0.5 L) and methanol (0.5 L) twice. The combined filtrates are concentrated under reduced pressure and the resulting tan residue is slurried in heptanes/ethyl acetate (7/3, 4×1 L) to yield 65 g of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)propionamide as a white powder. Yield 82%; ES-MS: m/z 375 [M+H], mp 191-192° C.
Reaction SMILES: [C:1]([CH:3]([CH:16]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17]1)[N:4]([CH3:15])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:2].[NH2:23][OH:24]>C(O)C>[NH2:2][C:1](=[N:23][OH:24])[CH:3]([N:4]([CH3:15])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:16]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17]1
Reactant: NO
Reactant: CN(C(=O)OCc1ccccc1)C(C#N)C1CCC(CO)C1
Solvent: CCO
Product: CN(C(=O)OCc1ccccc1)C(C(N)=NO)C1CCC(CO)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
To a solution of benzyl cyano(3-(hydroxymethyl)cyclopentyl)methyl(methyl)carbamate (0.540 g, 1.79 mmol) in ethanol (20 mL) was added 50% aqueous solution of hydroxylamine (0.07 mL, 2.15 mmol). The reaction mixture was stirred at 60° C. for 18 hours. The solvent was removed in vacuo to afford 0.610 g (76% yield) of title compound 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.43 (5 H, m), 7.14-7.23 (2 H, m), 5.18 (2 H, br s), 4.87-4.93 (1 H, m), 4.24 (1 H, m), 3.49-3.60 (2 H, m), 2.83-2.94 (3 H, br s), 2.60-2.71 (1 H, m), 2.11-2.49 (2 H, m), 1.60-2.11 (3 H, m), 1.25-1.55 (2 H, m). (+ESI, M+H+) 2 peaks m/z 336.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=4)[C:12]=3[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=2[CH3:35])[CH:5]=[CH:6][CH:7]=1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:13]2[C:12]3[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]([CH3:35])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:36](=[O:39])[CH2:37][CH3:38])[CH:3]=4)[C:16]=3[O:15][CH2:14]2)=[CH:18][CH:19]=1)([CH3:24])[CH3:25]
Reactant: CCC(=O)Cl
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N)c1)OCC2c1ccc(C(C)C)cc1
Product: CCC(=O)Nc1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Yield: 84 %

Procedure:
Using N-(7-(3-aminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 122 and propionyl chloride, the title compound was obtained in the same manner as in Example 121. Yield: 84%. Melting point: 237-239° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:43])([CH3:42])[C:40]#[N:41])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:40]([C:39]([C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:11][C:12]=3[CH:13]=2)=[O:25])=[CH:38][CH:37]=1)([CH3:43])[CH3:42])#[N:41]
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(C(C)(C)C#N)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 8.7 %

Procedure:
The title compound was prepared following the procedure described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.265 mmol), oxalyl chloride (0.2 mL), 2-(4-aminophenyl)-2-methylpropanenitrile (Intermediate-22, 0.063 g, 0.397 mmol), THF (5.0 mL), DIPEA (0.103 g, 0.795 mmol) and TEA (0.2 mL). The obtained crude product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.69 (s, 6H), 2.66 (s, 3H), 7.42 (t, J=7.8 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.61 (s, 3H), 7.82 (d, J=9.0 Hz, 2H), 9.45 (s, 1H), 10.11 (s, 1H), 11.58 (s, 1H); MS [M+H]+: 519.32.