Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:28])[CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](O)CN2C(=O)OC(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
To a stirred solution of methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl]methoxybenzoate (2.10 g, 5.98 mmol) in THF (60 ml) was added 60% oil NaH (359 mg, 8.97 mmol) at 0° C. After 15 minutes stirring, MeI (1.20 ml, 8.97 mmol) was added to the mixture was added at same temperature, and the resulting mixture was allowed to raise to room temperature for over 1 h. Then 60% oil NaH (359 mg, 8.97 mmol) and MeI (1.20 ml, 8.97 mmol) was added to the reaction mixture at room temperature and stirred for 14 h. The reaction mixture was poured into ice water and extracted with CHCl3. The combined extracts were washed with aq. NaHCO3 and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, n-hexane/EtOAc(4/1)], to give methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-methoxy-2-pyrrolidinyl]methoxybenzoate (1.32 g, 60%) as a colorless oil. 1H-NMR (CDCl3) δ 1.48 (s, 9H), 2.05 (m, 1H), 2.29 (d, J=14.2 Hz, 1H), 3.30 (s, 3H), 3.36–4.38 (m, 4H), 6.76 (br, 2H), 7.97 (d, J=8.8 Hz, 2H).
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Cl[CH2:53][C:54]1[N:58]([CH3:59])[N:57]=[C:56]([CH3:60])[CH:55]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:53][C:54]3[N:58]([CH3:59])[N:57]=[C:56]([CH3:60])[CH:55]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: Cc1cc(CCl)n(C)n1
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: Cc1cc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole and isolated as light yellow gum. MS (m/e): 371.3 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([O:11][C:12](=O)[O:13]C(C)(C)C)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][NH:5][CH3:6])[C:12](=[O:13])[O:11][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CNCCNC
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CNCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared as follows: N1,N2-dimethylethane-1,2-diamine (40 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (4.0 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h. the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl methyl(2-(methylamino)ethyl)carbamate. This amine was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z) -N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C31H46N2O4: 510.35; found 511 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[CH:6][CH:7]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CS(O)(=O)=O.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Cc1nc(-c2nnc[nH]2)ccc1Br
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Temperature: 68 °C

Procedure:
3-Bromo-2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridine (1 equiv), 3,4-dihydro-2H-pyran (2 equiv) and methanesulfonic acid (0.1 equiv) were combined in tetrahydrofuran. The reaction was heated to 68° C. for 3.5 h, cooled to room temperature, and treated with triethylamine (0.4 equiv). The reaction mixture was concentrated under reduced pressure, treated with acetonitrile and concentrated under reduced pressure at 35° C. The residue was dissolved in acetonitrile (1 volume) and water (2.25 volumes), and the solids were collected by filtration, washed with a solution of 20% acetonitrile in water and dried. The crude product was triturated with hexanes, filtered, washed with hexanes and dried to provide the desired product, as a solid. MS (ESI) m/z 324.9 [M+2]+.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2nc(S)oc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(N3CCN(C)CC3)oc2c1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (302 mg) was dissolved in anhydrous toluene (4 ml), the resulting solution was mixed with 2-mercapto-6-methylbenzoxazole (200 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (1.34 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)-6-methylbenzoxazole (166 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:24]4[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C#N)cc2)cn1
Yield: 13 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 4-cyanophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (13 mg, 13%) which was obtained as an off-white solid. MS: m/e=345.3[M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[N+:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1)([O-:12])=[O:11].[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29](Cl)=[O:30]>ClCCl>[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)=[O:30]
Reactant: O=[N+]([O-])c1ccnc(OC2CCNCC2)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1c(F)cccc1F)N1CCC(Oc2cc([N+](=O)[O-])ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Add triethylamine (2.57 mL, 18.5 mmol) to a suspension of 1.1 g (3.7 mmol) of 4-nitro-2-(piperidin-4-yloxy)-pyridine dihydrochloride in dry dichloromethane (50 mL). Then add 2,6-difluorobenzoyl chloride, 0.512 mL (4.07 mmol). Stir the mixture at room temperature overnight. Add water (50 mL) and separate organic layer. Dry with MgSO4 and filter. Evaporate solvents to obtain 1.22 g (91% yield) of (2,6-difluoro-phenyl)-[4-(4-nitro-pyridin-2-yloxy)-piperidin-1-yl]-methanone as a yellow solid (ES+(m/z)=364 [M+H].
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C(O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]([N+:1]#[C-:2])=[CH:11][N:12]([CH3:14])[CH3:13])[CH3:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: [C-]#[N+]C(=CN(C)C)C(=O)OCC

Procedure:
4-carboalkoxythiazoles are prepared essentially according to the procedure of Schollkopf, U., Porsch, P., Lau, H. Liebigs Ann. Chem. 1444 (1979). Thus, according to Method 55 and 56, reaction of ethyl isocyanoacetate with N,N-dimethylformamide dimethyl acetal in a suitable alcoholic solvent such as ethanol at room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. A solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:27](O)=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[CH:39]([CH2:52][CH:53]([CH3:55])[CH3:54])[NH:40][C:41](=[O:51])[CH:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(N[C@H](C(NCC(N[C@H](C(O)=O)C)=O)=O)CC1C=CC(O)=CC=1)=O)(C)(C)C.C(OC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1C=CC=CC=1)N)C1C=CC=CC=1>>[CH2:30]([O:37][C:38](=[O:56])[CH:39]([CH2:52][CH:53]([CH3:54])[CH3:55])[NH:40][C:41](=[O:51])[CH:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH:43][C:27](=[O:28])[CH:25]([CH3:26])[NH:24][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)CC(NC(=O)C(N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(NC(=O)CNC(=O)C(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)CC(NC(=O)C(Cc1ccccc1)NC(=O)C(C)NC(=O)CNC(=O)C(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-DL-tyrosylglycyl-DL-alanine and DL-phenylalanyl-DL-leucine benzyl ester are substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine and L-phenylalanyl-L-leucine benzyl ester, respectively in Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-DL-tyrosylglycyl-DL-alanyl-DL-phenylalanyl-DL-leucine benzyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[NH:9][C:8]2=O)(=[O:3])[CH3:2].S(Cl)([Cl:29])=O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2[Cl:29])(=[O:3])[CH3:2]
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Cl)c2cc1OC(C)=O

Procedure:
A mixture of the 7-methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (1.70 g, 4.79 mmol), thionyl chloride (30 mL) and anhydrous DMF (0.6 mL) were refluxed for 2.5 h. The volatiles were removed in vacuo and the residue dissolved in CH2CL2 (500 mL) and was washed with water, sat. NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate. (1.6 g, 4.23 mmol, 88%). HPLC retention time 9.75 min.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH2:1]([CH:8]1[CH2:10][N@@:9]1[S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@H]2CN2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)S(=O)(=O)[N@@]1CC1Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)[N@]1CC1Cc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a cooled (−10° C.) solution of (S)-2-benzylaziridine (100 g, 0.751 mol) and N,N-dimethylsulfamoyl chloride (84.5 mL, 0.787 mol) in dichloromethane (100 mL) was added N,N-diisopropylethylamine (131 mL, 0.751 mol). The resulting yellow solution was stirred at −10° C. for a minimum of 16 hours. After this period, a 0.5M solution of citric acid (500 mL) was added and the phases were separated. The organic phase was then washed with 1.0 M sodium bicarbonate solution (500 mL). The organic phase was then solvent exchanged into tert-butyl methyl ether (500 mL). The solution was then cooled to 0° C., and heptane (100 mL) was added dropwise over a period of 2 hours. The mixture was then aged for an additional 2 hours at 0° C., and then cooled (−10° C.), to allowed compound IIa to precipitate out as a white, crystalline solid (27.8 g, 77%). Tlc assay: Rf: 0.53 (SiO2; 1:1 heptane:ethyl acetate, KMnO4). 1H NMR (400 MHz, CDCl3): δ 7.20-7.29 (m, 5H), 2.94 (dd, J=14, 5 Hz, 1H), 2.80-2.88 (m, 1H), 2.70 (dd, J=14, 7 Hz, 1H), 2.66 (s, 6H), 2.56 (d, J=7 Hz, 1H), 2.14 (d, J=4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 137.4, 129.3, 128.9, 127.2, 40.6, 38.3, 38.1, 33.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C.[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2([CH2:60][NH2:61])[CH2:59][CH2:58]2)=[CH:53][CH:52]=1.Cl>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:61][CH2:60][C:57]2([C:54]3[CH:53]=[CH:52][C:51]([Cl:50])=[CH:56][CH:55]=3)[CH2:59][CH2:58]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: NCC1(c2ccc(Cl)cc2)CC1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C(=O)NCC2(c3ccc(Cl)cc3)CC2)cc1F
Temperature: 25 °C

Procedure:
To a mixture of 4-amino-3-fluorobenzoic acid (180.0 mg, 1.160 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 0.44 g, 1.2 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) at 0° C. were added N,N-diisopropylethylamine (0.61 mL, 3.5 mmol) and C-[1-(4-chloro-phenyl)-cyclopropyl]-methylamine; hydrochloride (303.7 mg, 1.392 mmol). The reaction mixture was slowly warmed to rt. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% methanol in chloroform).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[N:43]=[CH:44][O:45][C:46]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:37]2=[O:53])[S:31][C:32]=1[C:33](O)=[O:34].[NH2:54][CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[N:43]=[CH:44][O:45][C:46]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:37]2=[O:53])[S:31][C:32]=1[C:33]([NH:54][CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1)=[O:34]
Reactant: Cc1nc(N2CCN(Cc3ncoc3-c3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ncoc3-c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 13 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-((5-phenyloxazol-4-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)-pyridine, the title compound was obtained as a colorless solid in 13% yield: mp 78-81° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.72-7.69 (m, 3H), 7.50-7.36 (m, 3H), 7.30-7.27 (m, 1H), 6.04-6.00 (m, 1H), 4.68 (s, 2H), 4.58 (d, J=5.8 Hz, 2H), 4.11-4.05 (m, 2H), 3.73-3.67 (m, 2H), 2.62 (s, 3H); MS (ES+) m/z 475.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[NH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([NH:22][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[O:7])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2ccccc12)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 2-nitrobenzoyl chloride in anhydrous THF (5 mL) was added N, N-diisopropylethylamine (0.235 mL, 1.35 mmol) followed by 1-aminonaphthalene (192.9 mg, 1.35 mmol) and the solution was stirred at 40° C. for 16 hours. The solvent was evaporated to give N-naphthyl(2-nitrophenyl)carboxamide, a compound of formula (7), which was used for the next step without purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Product: N#Cc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1

Procedure:
Reaction of 4-fluorobenzonitrile with the compound of Example 4, step 1 following the procedure, of Example 1, step 2. affords the title compound, 4-[4-(2-Benzylamino-ethyl)-phenoxy]-benzonitrile, (2.7 g): 1H NMR (CDCl3, 300.00 MHz): 7.65-7.58 (m, 2H), 7.41-7.25 (m, 7H), 7.06-6.98 (m, 4H), 3.86 (s, 2H), 3.01-2.83 (m, 4H), m/z=328.9 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1
Reactant: O=Cc1ccoc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: c1cc(C2OCCO2)co1
Yield: 64.2 %

Procedure:
To a solution of furan-3-carbaldehyde (SM1-A, 2 g, 20 mmol) and ethane-1,2-diol (3.72 g, 60 mmol) in toluene (100 ml) was added pyridinium p-toluenesulfonate (PPTS, 50 mg, 0.2 mmol), and the solution was heated at reflux utilizing a Dean-Stark trap. After the theoretical amount of water was collected, the solvent was evaporated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give product (2-A) (1.8 g, 80%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.54 (s, 1H), 7.41-7.40 (t, 1H), 6.47-6.46 (d, 1H), 5.85 (s, 1H), 4.09-4.06 (m, 2H), 4.00-3.98 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](SC)[N:11]=[C:10]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.ClC1N=C(N2CCOC[C@@H]2C)C=C(C2C=NC=C(F)C=2)N=1.[CH:44]1([NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][C:54](B3OC(C)(C)C(C)(C)O3)=[C:53]([F:66])[CH:52]=2)=[O:49])[CH2:46][CH2:45]1>>[CH:44]1([NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([C:12]3[N:13]=[C:8]([C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:9]=[C:10]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH3:22])[N:11]=3)=[C:53]([F:66])[CH:52]=2)=[O:49])[CH2:46][CH2:45]1
Reactant: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Agent: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(Cl)n1
Product: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(-c2ccc(NC(=O)NC3CC3)cc2F)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoropyridin-3-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 7) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 11). Material was purified by prep HPLC twice (low pH) followed by purification using a TsOH cartridge (100 mg) to afford a yellow solid, (4.5 mg, 15%)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1.[S:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(OCC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:6]=1[C:7]([N:36]1[CH2:37][CH2:38][S:34][CH2:35]1)=[O:9]
Reactant: C1CSCN1
Reactant: CCCc1c(OC)ccc(C(=O)O)c1OCOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCc1c(OC)ccc(C(=O)N2CCSC2)c1OCOC
Reaction time: 0.25 h

Procedure:
Under argon atmosphere, a solution of 2-methoxymethoxy-3-n-propyl-4-methoxybenzoic acid (8 g) and 4-dimethylaminopyridine (0.38 g) in methylene chloride (150 ml) was cooled to 0° C., and to the solution was added N,N'-dicyclohexylcarbodiimide (7.8 g). The mixture was agitated for 15 minutes. Thiazolidine (3.0 ml) was added to the mixture, and the mixture was agitated at room temperature for another 15 hours. To the reaction mixture was added diethyl ether, and the mixture was filtered. Water and 1N aqueous hydrochloric acid were added to the filtrate, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel. There was obtained N-(2-methoxymethoxy-3-n-propyl-4-methoxybenzoyl)thiazolidine (9.0 g) from fractions eluted with n-hexane-ethyl acetate (2:1).