Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H](CC)C(N)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][C:15]1(C)[N:20]([O])C(C)(C)C[CH2:17][CH2:16]1.[Br-].[Na+].C(=O)([O-])[OH:28].[Na+]>ClCCl.O>[C:4]([O:3][C:1]([NH:20][C@@H:15]([CH2:16][CH3:17])[CH:14]=[O:28])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: O=C([O-])O
Reactant: CC[C@H](C(=O)OC(C)(C)C)C(N)O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 77 %

Procedure:
To a solution of 2(S)-Boc-aminobutanol (50 g; 264 mmol) in dichloromethane (500 mL) and water (350 mL) were added at 20° C. TEMPO (0.01 eq), sodium bromide (1 eq) and sodium hydrogencarbonate (3 eq). The reaction mixture was stirred at 0° C. and diluted bleach (1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at 0° C. and then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuo to dryness, giving 2(S)-(tert-butoxycarbonyl)aminobutyraldehyde as a low-melting solid (38.1 g; yield: 77%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[Cl:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:15].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([O:14][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: ClCc1cccs1
Reactant: Cc1csc(Nc2ncccc2O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccs2)n1
Product: Cl
Yield: 14.4 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 200 mg, 0.96 mmol), 2-(chloromethyl)thiophene (160 mg, 0.96 mmol) and potassium carbonate (333 mg, 2.4 mmol) were reacted according to Example 3, Step B, to provide the title compound (47 mg, 14% yield) as a tan solid. 1H NMR (d6-DMSO) δ 10.90 (bs, 1H), 7.98 (m, 1H), 7.69 (m, 1H), 7.59 (m, 1H), 7.35 (m, 1H), 7.12 (m, 1H), 7.06 (m, 1H), 6.83 (s, 1H), 5.52 (s, 2H), 2.31 (s, 3H). Mass spectrum (apci) m/z=304 (M+H-HCl).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=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.C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH:41]=[CH2:42].O>C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:42][CH:41]=[CH2:40])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCI
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6.86 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetate [Step A of Example 14], 3.51 g of potassium carbonate, 15 ml of diemethylformamide and 7 ml of allyl iodide was stirred under an inert atmosphere at room temperature for 5 hours and then 250 ml of water and 150 ml of ethyl acetate were added thereto with stirring. The mixture was decanted and the aqueous phase was washed and reextracted with ethyl acetate. The extracts were dried, vacuum filtered and evaporated to dryness. The residue was taken up in ethanol and crystallizaton was started. The mixture was cooled in an ice bath with stirring for half an hour and was then vacuum filtered. The crystals were rinsed with ethanol to obtain 4.72 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-propenyloxyimino)-acetate. 215 mg of the product were dissolved in 2 ml of ethanol and 2 ml of methylene chloride and the mixture was filtered. The filtrate was concentrated and diluted with ethanol. Crystallization was effected in an ice bath and the mixture was vacuum filtered. The crystals were rinsed with ethanol and dried to obtain 70 mg of the pure product which melted at 90° C. (pasty) and 160° C. (pure).
Reaction SMILES: [OH:1][CH:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][C:4](=[O:16])[N:3]1[CH3:17].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:6]=2[CH2:5][C:4](=[O:16])[N:3]1[CH3:17]
Reactant: Cc1ccc2[nH]c3c(c2c1)C(O)N(C)C(=O)C3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC(=O)N(C)C1O

Procedure:
The title compound is prepared from a mixture of 1,2-dihydro-1-hydroxy-2,8-dimethyl-4H-pyrido[4,3-b]indol-3(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]1[N:34]=[C:33]([N:35]2[C:43](=[O:44])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]2=[O:45])[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CC#N>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:33]1[N:34]=[C:29]([CH2:28][N:11]([CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1cccc(N2C(=O)c3ccccc3C2=O)n1)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione, 2-(6-bromomethyl-pyridin-2-yl)-isoindole-1,3-dione (Goswami, S. et al. J. Am. Chem. Soc. 1989, 111, 3425-6), and DIPEA in CH3CN gave 2-{4-[[6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridin-2-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a tan solid. Deprotection with hydrazine following General Procedure E gave the free base. Conversion to the HBr salt using General Procedure D gave COMPOUND 355 as a white solid. 1H NMR (D2O) δ 1.51-1.55 (m, 4H), 1.71-1.85 (m, 1H), 1.91-2.03 (m, 1H), 2.13-2.18 (m, 1H), 2.32-2.36 (m, 1H), 2.46-2.54 (m, 1H), 2.67-2.74 (m, 1H), 2.90-2.99 (m, 4H), 3.98 (s, 2H), 4.38 (dd, 1H, J=5.7, 10.8 Hz), 6.90-6.96 (m, 2H), 7.80-7.86 (m, 2H), 8.30(br d, 1H, J=8.1 Hz), 8.58 (br d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 20.00, 20.43, 25.14, 25.26, 27.63, 39.57, 51.24, 52.88, 59.64, 113.08, 113.21, 125.70, 139.29, 140.38, 145.05, 146.08, 147.71, 151.86, 154.94; ES-MS m/z 326 (M+H). Anal. Calcd. for C19H27N5.3.4HBr.1.8H2O: C, 36.05; H, 5.41; N, 11.06; Br, 42.92. Found: C, 35.93; H, 5.24; N, 10.91; Br, 43.14.
Reaction SMILES: O=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13].C>O1CCOCC1>[N-:9]=[C:4]=[O:3].[CH3:2][O:16][C:15](=[O:17])[C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH2:9]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CC(C)C
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of leucine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give leucine methyl ester isocyanate.
Reaction SMILES: [C:1]([NH2:9])(=O)[C:2]1C=CC=CC=1.[C:10]([O:14][C:15](=[O:42])[C@@H:16]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:17][C:18](=[O:34])[NH:19][N:20]=[C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:13])([CH3:12])[CH3:11].C(O)(C(F)(F)F)=O.[CH:50]([NH2:53])(C)C.[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:60][C:61](=[O:77])[NH:62][N:63]=[C:64]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([CH3:56])[CH3:55]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:42])[C@@H:16]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:17][C:18](=[O:34])[NH:19][N:20]=[C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:13])([CH3:11])[CH3:12].[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:60][C:61](=[O:77])[NH:62][N:63]=[C:64]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([CH3:56])[CH3:55].[CH:54]([NH:57][C:58](=[O:85])[C@@H:59]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:60][C:61](=[O:77])[C:50](=[C:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:53][NH:9][C:1]#[CH:2])([CH3:55])[CH3:56]
Reactant: CC(C)N
Reactant: NC(=O)c1ccccc1
Agent: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)NN=C(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CNNC(C(=O)N[C@H](Cc1ccccc1)C(=O)NC(C)C)=C(c1ccccc1)c1ccccc1

Procedure:
With these cyclization conditions in hand, N-acyl amino imidazolin-2-one amide 14 was synthesized to study the conformation of this model system in the solid state and in solution, using X-ray crystallography and NMR spectroscopy, respectively (Scheme 2). Benzhydrylidene aza-glycinyl-D-phenylalanine isopropyl amide 9 was prepared from benzhydrylidene aza-glycinyl-D-phenylalanine tert-butyl ester 7 by tertbutyl ester cleavage in a 1:1 v/v mixture of TFA: DCM, followed by coupling to iso-propylamine using a mixed anhydride approach.xx Employment of amide 9 in the alkylation and cyclization steps minimized racemization, likely due to preferential amide nitrogen deprotonation inhibiting removal of the α-hydrogen. Indeed, in comparison to the alkylation of aza-glycinyl-D-phenylalanine tert-butyl ester 7, the chemoselective alkylation of semicarbazone 9 gave aza-propargyl glycinamide 10 in 71% yield with no detectable racemization (see above). Subsequent NaH-promoted 5-exo-dig cyclization gave imidazolin-2-one 11, possessing an exocyclic double bond, in a 57% yield. However, olefin migration occurred upon hydrazone removal, using hydroxylamine hydrochloride in pyridine 11 to afford N-amino imidazalone 12, which without further purification was treated with 4-methoxybenzoyl chloride to provide N-acyl dipeptide amide 14 in 56% yield.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:4][N:5]([CH3:7])[CH:6]=1.[Li]CCCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3]1[C:2]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:6][N:5]([CH3:7])[N:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)c(-c2ccccc2F)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.9 %

Procedure:
To a solution of 4-bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole (3.03 g, 11.9 mmol, 1.0 eq.) in THF (40 mL) under nitrogen at −78° C. was added nBuLi (hexane, 2.5 M, 5.3 mL, 13.2 mmol, 1.1 eq.) over 10 min. After 45 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.7 mL, 13.2 mmol, 1.1 eq.) was added. After 1 h 45 min, saturated aqueous NH4Cl and EtOAc were added. The cold bath was removed, and the reaction mixture was stirred to room temperature. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (3:1) as eluent afforded 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (1.83 g, 51% yield).
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:39]([O:43][C:44](=[O:47])[CH2:45]Br)([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:43][C:44](=[O:47])[CH2:45][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:35][CH2:36][CH2:37][CH3:38])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1)=[O:24])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Reactant: CC(C)(C)OC(=O)CBr
Product: CCCCN(CCCC)C(=O)c1cn(CC(=O)OC(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Yield: 79.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 264K, methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (310 mg, 0.6 mmol) and t-butylbromoacetate (117 mg, 0.6 mmol) were converted to the title compound (300 mg, 90%). MS(ESI+) m/z 631.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:21][O:20][CH2:19][CH2:18][CH2:17][N:8]1[C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=[C:9]1[C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=2)[CH2:12]1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2cccc(Cl)c21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21

Procedure:
((R)-7-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (0.111 mmol max, about half of crude oil from Step E) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.122 mmol, 0.040 g) and N-methylmorpholine (0.555 mmol, 0.061 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.122 mmol, 0.046 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (20-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (30F) as a clear oil that was used directly onto the next step. ESI-ESI-MS: m/z 619.5 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH2:14][C:13]([NH2:17])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C=O.[C:20]([O-])(=O)C.[NH4+].[H][H]>[Ni].CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH:14]([CH3:20])[C:13]([NH2:17])=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(=O)[O-]
Reactant: CS(=O)(=O)c1ccc(N2N=C(N)CC2=O)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: C=O
Agent: [NH4+]
Solvent: CO
Product: CC1C(=O)N(c2ccc(S(C)(=O)=O)cc2)N=C1N

Procedure:
In a 3 liter autoclave were placed: 151.8 g (0.6 mole) of 1-(p-methylsulphonylphenyl)-3-amino-2-pyrazolin-5-one, 27 g (0.9 mole) of paraformaldehyde, 115.5 g (1.5 mole) of ammonium acetate, 60 g of Raney nickel and 1735 ml of methanol. The autoclave was charged with hydrogen to a pressure of 1500 psi. After reduction for 2 h at 100° C the catalyst was filtered off and the filtrate was neutralized by addition of 100 ml of concentrated hydrochloric acid. The filtrate was concentrated by evaporation and the residue was diluted by addition of 300 ml of water. The precipitate was separated and treated with boiling acetonitrile. Yield: 65 g (40%). Melting Point: 239°-240° C.
Reaction SMILES: [CH2:1]([C:3](O)([CH2:6][CH2:7][CH:8]=[C:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:4]=[CH2:5])[CH3:2].P(Br)(Br)[Br:17]>>[Br:17][CH2:2][CH:1]=[C:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: C=CC(O)(CC)CCC=C(C)CC(C)C
Reactant: BrP(Br)Br
Product: CCC(=CCBr)CCC=C(C)CC(C)C

Procedure:
By the procedure described in Example 2, 33.65 g. of 3-ethyl-7,9-dimethyl-1,6-decadien-3-ol and 6.6 ml. of phosphorus tribromide are reacted to produce 1-bromo-3-ethyl-7,9-dimethyl-2,6-decadiene.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:23]([N:30]1[C:13]2[N:14]=[C:15]([Cl:19])[C:16]([F:18])=[CH:17][C:12]=2[C:10](=[O:11])[N:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:31]1=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Yield: 82.3 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with benzyl isocyanate (1.17 mL, 9.51 mmol) in DMA afforded crude product. Recrystallization from chloroform provided 2.15 g of the title compound as a solid, mp 209-210° C.
Reaction SMILES: [CH3:1][CH:2]1[O:10][C:5]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[O:10][C:5]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1
Reactant: CC1CN2CC(C)OC2(CCCCCO)O1
Reactant: C=C(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCC12OC(C)CN1CC(C)O2
Temperature: 0 °C
Yield: 462 %

Procedure:
In an oven dried 100 mL round-bottom flask equipped with a pressure equalizing addition funnel and a reflux condenser were added 5-(2,6-Dimethyl-tetrahydro-oxazolo[2,3-b]oxazol-7a-yl)-pentan-1-ol (22.9 g, 0.01 mol) followed by chloroform 50 mL and triethylamine 12.12 g, 0.12 mol). The reaction content was cooled to 0° C. under nitrogen. While stirring a solution of methacryloyl chloride (11.44 g, 0.11 mol) in chloroform was added slowly. After completion of the acid chloride the reaction was stirred one hour at 0° C., then allowed to warmed to room temperature and then stirred over night at room temperature. The triethylamine salt was filter off through Celite® (World Minerals, Santa Barbara, Calif.), the filtrate concentrate at reduced pressure. NMR (proton) showed this material to be the desired material contaminated with triethyl amine salt. This material was then washed with hexanes (2×125 ml), the hexanes washes combined concentrated giving 13.74 g of product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[N:21]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:30]2)[N:21]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)ccc3C#N)C2)nc1N
Temperature: 120 °C

Procedure:
55 mg (0.19 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 60.9 mg (0.23 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 11A) and 0.169 ml (0.97 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 30 mg (33% of theory) of the product were obtained in solid form.
Reaction SMILES: [C:1]([C:6]1[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]([OH:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19].P(Cl)(Cl)Cl>C1(C)C(C)=CC=CC=1>[C:1]([C:6]1[CH:14]=[C:10]([C:11]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[CH3:16])=[O:13])[C:9]([OH:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: CCC(C)(C)c1ccc(O)c(C(=O)O)c1
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCC(C)(C)c1ccc(O)c(C(=O)Nc2ccc([N+](=O)[O-])cc2C)c1
Temperature: 70 °C
Yield: 55 %

Procedure:
A mixture of 10.4 g of 5-tert-amylsalicylic acid and 7.6 g of 2-methyl-4-nitroaniline in 100 ml of xylene is heated at 70° C and to the mixture is added a solution of 2.6 g of phosphorus trichloride in 10 ml of xylene. The whole mixture is refluxed for two and a half hours. The hot reaction solution is decanted. The supernatant solution is cooled on an ice bath. The crystalline precipitate is collected by filtration. Recrystallization from methanol gives 9.4 g of the title compound as pale yellow crystals, melting at 150°-151° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].[OH-].[Na+]>C(O)(C)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:28]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:27]=2)=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30]
Reactant: Cc1ccc(NC(=N)N)cc1[N+](=O)[O-]
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 104130488 %

Procedure:
3-Dimethylamino-1-(3-pyridyl)-2-propen-1-one (20 g, 0.1 μmol), 4-methyl-3-nitrophenyl-guanidine nitrate (32 g, 0.12 mol), and sodium hydroxide (6.8 g, 0.17 mol) were dissolved in isopropanol, and reacted under reflux for 28 hours. The reaction solution was cooled to 0° C., filtered, washed with isopropanol, water and ethanol, and dried to give N-(4-methyl-3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (32 g).