Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH:18]([N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:23])[C:19]([OH:21])=O)=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][CH:18]([N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH3:23])[C:19]([NH:64][C@@H:63]([CH2:62][S:61][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:65]([NH2:67])=[O:66])=[O:21])=[CH:31][CH:32]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:2]=[CH2:3]
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
2.24 g (3.86 mmol) of the compound from example 7A was dissolved in 100 ml dichloromethane. 1.401 g (3.86 mmol) S-Trityl-L-cysteinamide, 0.67 ml (3.86 mmol) N,N-diisopropylethylamine and 1.47 g (3.86 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 3.26 g (2.75 mmol, 71% of theory, 78% purity) of the desired product as a mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:36][C:37]1[N:38]=[CH:39][C:40]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:41][CH:42]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
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: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)cn1
Temperature: 95 °C
Yield: 51.9 %

Procedure:
A mixture of Example C1 (0.200 g, 0.479 mmol), K2CO3 (0.132 g, 0.957 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.126 g, 0.574 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.055 g, 0.048 mmol), sparged again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3 and extracted with EtOAc (4×). The combined organics were dried over Na2SO4, concentrated to dryness, suspended in MeCN and sonicated. The resulting solid was collected via filtration and dried to afford N-(5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (118 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1 H), 9.09 (d, J=2.3 Hz, 1 H), 8.54 (d, J=5.7 Hz, 1 H), 8.29-8.24 (m, 2 H), 8.07 (d, J=9.0 Hz, 1 H), 7.75 (dd, J=9.0, 2.9 Hz, 1 H), 7.63 (d, J=2.4 Hz, 1 H), 7.33 (d, J=8.2 Hz, 1 H), 6.87 (dd, J=5.7, 2.4 Hz, 1 H), 3.92-3.77 (m, 5 H), 3.48-3.34 (m, 4 H), 2.50 (s, 3 H), 1.77-1.65 (m, 2 H), 1.62-1.55 (m, 2H); MS (ESI) m/z: 475.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:32])[C:9](=[O:31])[NH:10][C:11]2[CH:12]=[C:13]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N:44]1([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=2)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[CH3:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:12][C:11]=1[NH:10][C:9]([N:8]([CH3:32])[C:4]1[CH:3]=[C:2]([NH:56][C:53]2[CH:52]=[CH:51][C:50]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:55][CH:54]=2)[N:7]=[CH:6][N:5]=1)=[O:31]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)N(C)c1cc(Cl)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)N(C)c1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
N-{3-[3-(6-Chloro-pyrimidin-4-yl)-3-methyl-ureido]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (50 mg, 0.107 mmol) and p-toluenesulfonic acid (20 mg, 0.105 mmol) were mixed and dissolved in 1 ml DMF. Then 4-Morpholin-4-yl-phenylamine (22 mg, 0.11 mmol) was added to it. The reaction was stirred at 80° C. for 10 hours. The crude product was purified by reverse phase HPLC to give final product N-(4-Methyl-3-{3-methyl-3-[6-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-ureido}-phenyl)-3-trifluoromethyl-benzamide as grey solid, 48 mg; 1H NMR 600 MHz (DMSO) δ 12.74 (s, 1H), 10.46 (s, 1H), 9.53 (s, 1H), 8.47 (s, 1H), 8.41 (m, 1H), 8.31 (s, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.97 (d, 1H, J=7.2 Hz), 7.79 (t, 1H, J=4.2 Hz), 7.52 (d, 1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.22 (d, 1H, J=8.4 Hz), 6.99 (s, 1H), 6.98 (s, 1H), 6.34 (s, 1H), 4.15 (m, 4H), 3.76 (m, 4H), 3.10 (m, 3H), 2.32 (s, 3H); MS m/z 606.2 (M+1).
Reaction SMILES: [OH:1]C(CCCCC)CCC1N(CCCCCCC(O)=O)C(=O)CS1.[OH:25][CH:26]([CH2:44][O:45][CH2:46][CH2:47][CH3:48])[CH2:27][CH2:28][CH:29]1[N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:32](=[O:43])[CH2:31][S:30]1>>[OH:25][CH:26]([CH2:44][O:45][CH2:46][CH2:47][CH3:48])[CH2:27][CH2:28][CH:29]1[N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:32](=[O:43])[CH2:31][S:30]1=[O:1]
Reactant: CCCOCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Reactant: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Product: CCCOCC(O)CCC1N(CCCCCCC(=O)O)C(=O)CS1=O

Procedure:
This compound is prepared essentially by the method described in Example 2 except that the 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid is replaced by 7-[2-(3-hydroxy-4-propoxybutyl)-4-oxo-3-thiazolidinyl]heptanoic acid. Column chromatography of the resulting product provides the title compound as a t.l.c. homogeneous oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]([F:21])([F:22])[F:23])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (70 mg, 0.44 mmol), 4-hydroxy-3-(trifluoromethyl)benzonitrile (91 mg, 0.49 mmol), K2CO3 (92 mg, 0.66 mmol) in DMF (2 mL) was stirred at 50° C. overnight. Water (4 mL) was added and a precipitate was formed. The solid was filtered-off and it was triturated with MeOH to give the title compound (85 mg) as a brownish solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.CN1CCOCC1.[CH3:30][N:31]([CH3:48])[C:32]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:37][CH2:36][CH:35]([CH2:38][C:39](O)=[O:40])[CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+]>O.CN(C)C=O>[CH3:48][N:31]([CH3:30])[C:32]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:33][CH2:34][CH:35]([CH2:38][C:39]([NH:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:40])[CH2:36][CH2:37]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccn2)CCC(CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccn2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Reaction time: 16 h

Procedure:
1-Hydroxybenzotriazole (432 mg, 3.2 mmol), tryptamine (256 mg, 1.6 mmol) and N-methylmorpholine (0.352 ml, 3.2 mmol) were added to a solution of the more polar diastereoisomer of (4-dimethylamino-4-pyridin-2-yl-cyclohexyl)-acetic acid (476 mg, 1.6 mmol) in abs. dimethylformamide (20 ml) under argon. The solution was cooled in an ice-bath, dicyclohexylcarbodiimide (660 mg, 3.2 mmol) was added and the mixture was stirred at RT for 13 d, during which dicyclohexylurea precipitated out. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 16 h. The crude product thereby precipitated out as a beige-coloured oily compound (319 mg, 49%). After purification by chromatography on silica gel (45 g) with methanol and methanol/30 percent strength aqueous ammonia (100:1), the product was obtained as a beige-coloured oil in a yield of 12% (80 mg).
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:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 85 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (93 mg, 85%) which was obtained as an off white solid. MS: m/e=365.4 [M+H]+.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 53.9 %

Procedure:
Following the procedure of Example 3, step 4, 40.0 mg (0.214 mmol) of trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in anhydrous DMF (2 ml) was reacted with 32.5 mg (0.235 mmol) of anhydrous potassium carbonate and 25.4 ml (0.214 mmol) of benzyl bromide. Chromatography on flash silica, eluting with 10-15% ethyl acetate/petroleum ether, gave 32.0 mg (54%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 244°-248° C. (dec). NMR δ(D2O) 1.49-1.84 (4H, m), 2.68 (2H, m), 2.89-2.99 (3H, m), 3.23 (1H, m), 3.53 (1H, m), 3.73 (1H, m), 4.37 (2H, m), 7.23-7.27 (3H, m), 7.33 (1H, m), 7.54 (5H, s). m/z (CI+, NH3) 278 (M+H)+, 186 (M-CH2Ph)+, 184, 110.
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH3:16][N:17]([CH3:29])[C@@H:18]1[CH2:27][CH2:26][C:25]2[C:24](O)=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19]1.CCN(CC)CC>C(Cl)Cl.[Cl-].[Na+].O>[F:6][C:5]([F:8])([F:7])[S:2]([O:1][C:24]1[C:25]2[CH2:26][CH2:27][C@@H:18]([N:17]([CH3:29])[CH3:16])[CH2:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)[C@@H]1CCc2c(O)cccc2C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)[C@@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
Tf2O (4.3 mL, 25.452 mmol) was dropwise added to a −78° C. cooled solution of (6R)-6-(dimethylamino)-5,6,7,8-tetrahydronaphthalen-1-ol (4.25 g, 22.218 mmol) and Et3N (8.0 mL, 57.396 mmol) in CH2Cl2 (90 mL). The reaction was completed after 5 min at low temperature. The reaction mixture was poured into brine (200 mL) and extracted with CH2Cl2 (2×200 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was flash chromatographed on silica gel (5-10% MeOH/CH2Cl2) to furnish 5.10 g of the title product (Rf=0.4 (10% MeOH/CH2Cl2), pale brown colored oil, 71% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(Cl)[Cl:12]>>[CH3:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([Cl:12])[CH:4]=1)=[O:10]
Reactant: ClCCl
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(O)c(Cl)c1

Procedure:
50 gm of p-hydroxyacetophenone were dissolved in 500 ml of hot methylene dichloride and filtered through a small pad of silica gel. The solution was allowed to cool and the methylene dichloride was stripped off to obtain 41.75 gm (0.31 mol) of crystals. These crystals were dissolved in about 1.5 liters of methylene dichloride. The reaction flask was placed in an ice bath and chlorine gas was bubbled through the solution. After about a total of 5 minutes of Cl2(g) bubbling, the methylene chloride was stripped off to yield more than 30 gm of white crystals (>90% pure) of 3-chloro-4-hydroxy acetophenone.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)=O)[C:5](=O)[CH2:4][CH2:3]1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1>>[CH3:1][CH:2]1[CH2:3][CH2:4][C:5]2[N:23]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[C:9]([C:11]3[CH:12]=[CH:13][C:14]4[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=4[CH:21]=3)=[CH:8][C:6]=2[CH2:7]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1CCC(=O)C(CC(=O)c2ccc3c(c2)NC(=O)CO3)C1
Product: CC1CCc2c(cc(-c3ccc4c(c3)NC(=O)CO4)n2-c2ccc(C(=O)O)cc2)C1
Yield: 60 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 6-[(5-methyl-2-oxocyclohexyl)acetyl]-2H-1,4-benzoxazin-3(4H)-one and 4-aminobenzoic acid, the title compound was isolated in 60% yield (98% purity by HPLC). MS(ESI+): 403.7; MS(ESI−): 401.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCc1conc1-c1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1conc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of methyl 3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionate (2.40 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propan-1-ol (2.06 g, yield 95%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 62–63° C.
Reaction SMILES: [Na].[Br-].[CH3:3][C:4]1([CH3:10])[NH:8][C:7]([NH2:9])=[N:6][CH2:5]1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([O-])=[O:14]>CO>[OH:16][C:11]1[N:9]=[C:7]2[NH:8][C:4]([CH3:10])([CH3:3])[CH2:5][N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC1(C)CN=C(N)N1
Agent: [Br-]
Agent: [Na]
Solvent: CO
Product: CC1(C)Cn2c(nc(O)cc2=O)N1
Yield: 99.2 %

Procedure:
To 250 mL of methanol under nitrogen, 5.21 g of sodium are added. Once dissolution is total and after returning to RT, 20 g of 5,5-dimethyl-4,5-dihydro-imidazol-2-amine bromide and 31.2 g of ethyl malonate are added. The medium is heated with reflux for 16 h. The reaction medium is dry concentrated, and then taken up in 40 mL of ice water. The expected product is precipitated by adding 1N HCl. The obtained precipitate is filtered, washed with water and then dried in the oven at 50° C. 18.62 g (yield=97%) of 7-hydroxy-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][N:14]1[CH:18]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[N:16]=[CH:15]1>>[CH3:13][N:14]1[CH:18]=[C:17]([S:19]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:20])[N:16]=[CH:15]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cn(C)cn2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 1-methylimidazole-4-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (3.2 mg) with purity >90%. LCMS (pos) m/z 331.0.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[C:12]1([S:18]([C:21]2[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[C:12]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of benzimidazole (11.8 g, 0.10 mol) in DMF (500 ml), is added, at room temperature under nitrogen, sodium hydride (60% in mineral oil, 4.4 g, 0.11 mol), and the mixture is stirred for 10 min. The mixture is admixed with 4-chlorophenyl phenyl sulfone (26.1 g, 0.10 mol) and stirred at 100° C. for 16 h. After again adding sodium hydride (60% in mineral oil, 2.0 g, 0.05 mol) at room temperature, the mixture is stirred at 130° C. for 16 h. After cooling to room temperature, the mixture is added to ice-water. Precipitated product is filtered off and washed with water. Yield: 91%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10]=[CH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[CH2:10]([C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:11]
Reactant: C=Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1ncccc1N
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 0.220 g (1.47 mmol) of 3-nitro-2-vinyl-pyridine dissolved in 1:1 methanol/ethyl acetate was added 0.010 g of Pd/C. The resulting mixture was hydrogenated overnight at 50 psi. Filtration and removal of solvent provided 0.160 g (89% yield) of 2-ethyl-pyridin-3-ylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CCCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH2:20][C:30]([C:25]3[CH:26]=[C:27]([Cl:29])[CH:28]=[C:23]([Cl:22])[CH:24]=3)([OH:35])[C:31]([F:34])([F:33])[F:32])=[CH:17][CH:18]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(C2(F)CN(C(=O)OC(C)(C)C)C2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(O)(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Temperature: 60 °C

Procedure:
In a clean and dry seal tube, to a stirred solution of 3-(4-acetyl-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (4 g, 13.652 mmol, 1eq.) in heptane (40 mL) was added 1-(3,5-dichlorophenyl)-2,2,2-trifluro-ethanone (6.60 gm, 27.304 mmol, 2eq.) followed by addition of triethyl amine (TEA, 3.80 ml, 27.304 mmol, 2eq.) at room temperature. Resulting reaction mixture was heated at 60° C. for 16 hours. After maximum consumption of starting material, reaction mixture was cooled to room temperature, solid precipitated out. Solid was filtered over Buchner funnel and washed with heptane (2×30 mL) and n-Pentane (70 mL) and dried under reduced pressure to get product as white solid. Yield: −5.0 g (68.31%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.68 (d, J=17.36 Hz, 1H), 3.85 (d, J=17.44 Hz, 1H), 4.17-4.24 (m, 2H), 4.39-4.47 (m, 2H), 5.69 (s, 1H), 7.33-7.35 (m, 1H), 7.48 (d, J=1.16 Hz, 2H), 7.62 (d, J=8.44 Hz, 2H), 7.98 (d, J=8.28 Hz, 2H). LC-MS (m/z): =534.0 (M−H).
Reaction SMILES: N(OS(=O)(=O)O)=O.N[C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1.[CH3:22][OH:23]>C(O)(=O)C>[CH3:22][O:23][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1
Reactant: CNC1C=Cc2cc(N)ccc2CC1
Reactant: CO
Agent: O=NOS(=O)(=O)O
Solvent: CC(=O)O
Product: CNC1C=Cc2cc(OC)ccc2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.1 g of nitrosyl sulfuric acid were added over 10 minutes at 20° C. to a mixture of 6 g of 2-amino-7-methylamino-6,7-dihydro [5H] benzocycloheptene in 60 ml of acetic acid and the mixture was stirred 2 hours at room temperature. The resulting brown solution was poured into 300 ml of methanol and the mixture was refluxed for 45 minutes and was evaporated to dryness under reduced pressure. The residue was added to 150 ml of water and the neutral fraction was removed by extraction twice with 100 ml of ether. The mixture was alkalinized at 10° C. by addition of sodium hydroxide and was extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 3.7 g of raw product. The latter was chromatographed over silica gel and was eluted with a 7-2-1 chloroform-methanol-triethylamine mixture to obtain a homogenous fraction of 3.4 g of 2-methoxy-7-methylamino-6,7-dihydro [5H] benzocycloheptene in the form of a yellow oil.