Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:18]([OH:20])=O)[CH2:11][C@@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[CH2:21]([NH2:24])[CH2:22][CH3:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:8][C@@:9]1([C:18]([NH:24][CH2:21][CH2:22][CH3:23])=[O:20])[CH2:11][C@@H:10]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)C[C@@H]1c1ccccc1
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)[C@]1(N)C[C@@H]1c1ccccc1
Yield: 85 %

Procedure:
The title compound was prepared by coupling commercially available (1S,2R)-1-[(tert-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid with n-propylamine in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and subsequent Boc detachment with trifluoroacetic acid (yield: 85% of theory over both stages).
Reaction SMILES: [OH:1][CH:2]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][Si:17]([O:22][CH3:23])([O:20][CH3:21])[O:18][CH3:19])[CH2:3][N:4]=[C:5]([N:9]([CH3:11])[CH3:10])[N:6]([CH3:8])[CH3:7].[N:24]([CH2:27][CH2:28][CH2:29][Si:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[C:25]=[O:26]>C1(C)C=CC=CC=1>[CH2:35]([O:34][Si:30]([O:37][CH2:38][CH3:39])([O:31][CH2:32][CH3:33])[CH2:29][CH2:28][CH2:27][NH:24][C:25](=[O:26])[O:1][CH:2]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][Si:17]([O:22][CH3:23])([O:18][CH3:19])[O:20][CH3:21])[CH2:3][N:4]=[C:5]([N:9]([CH3:10])[CH3:11])[N:6]([CH3:7])[CH3:8])[CH3:36]
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Reactant: CO[Si](CCCOCC(O)CN=C(N(C)C)N(C)C)(OC)OC
Solvent: Cc1ccccc1
Product: CCO[Si](CCCNC(=O)OC(CN=C(N(C)C)N(C)C)COCCC[Si](OC)(OC)OC)(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A ten gram sample of N"-[2-hydroxy-3-[3-(trimethoxysilyl)propoxy]propyl]-N,N,N',N'-tetramethylguanidine, prepared in Example 2, was dissolved in 5 g of toluene. To this solution was added, under a stream of argon gas, 7.1 g of 3-isocyanatopropyltriethoxysilane. The resulting mixture was stirred at ambient temperature for one hour. At the end of this time, analysis of the reaction mixture by infrared spectroscopy indicated the absence of hydroxyl function. The reaction mixture, containing 71% by weight of [3-(triethoxysilyl)propyl]carbamic acid, [2-[[bis(dimethylamino)methylene]amino]-1-[[3-(trimethoxysilyl)propoxy]methyl]ethyl]ester, was used without further puriofication as an accelerator.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: Cc1cccc(Cl)c1CN
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1CNC1=NC(=O)CS1

Procedure:
Similar procedure as described in example 15a was used, starting with 2-chloro-6-methyl-benzylamine, rhodanine, mercuric chloride and DIEA to give 2-(2-chloro-6-methyl-benzylamino)-thiazol-4-one. LC-MS m/e 259 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25]>>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([CH3:16])=[C:11]([NH:15][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)S(=O)(=O)Cl
Product: Cc1c(NS(=O)(=O)C(C)C)cccc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
The product from Example 2B and isopropylsulfonylchloride were processed as described in Example 3 to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ1.23 (d, 6H, J=6.5 Hz), 2.39 (s, 3H), 3.18 (m, 1H), 4.04 (s, 4H), 6.91 (dd, 1H, J=7.5, 1.6 Hz), 6.97 (m, 2H), 7.19 (m, 2H), 7.26 (m, 8H), 8.86 (s, 1H); MS (APCI+) m/z 409 (M+H)+.
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([CH3:8])=[CH:6][CH:5]=1)[CH3:3].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[N+:25]([O-:27])=[O:26].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:22]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[C:16]=1[CH:8]=[C:7]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:2][CH3:3])[CH:5]=[CH:6]1)([O-:24])=[O:23]
Reactant: CC[n+]1ccc(C)c2ccccc21
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN1C=CC(=Cc2c([N+](=O)[O-])cccc2[N+](=O)[O-])c2ccccc21
Reaction time: 8 h
Yield: 25 %

Procedure:
1-Ethyllepidinium iodide (3.0 g., 10 mmole) and 1-chloro-2,6-dinitrobenzene (2.5 g., 12 mmole) are warmed in acetonitrile (50 ml.) and diisopropylethylamine (2.6 g., 20 mmole) is added. The resulting dark mixture is aligned to cool and stand overnight. The precipitate of dye is filtered off and washed with acetonitrile and ether. On recrystallization from acetonitrile, 25% yield (0.85 g.) of purified dye is obtained with a m.p. of 45°-155° C. dec.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].CCN(CC)CC.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[NH2:1]/[C:2](/[CH3:6])=[C:3](\[C:24]1[CH2:25][CH2:26][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH:23]=1)/[C:4]#[N:5]
Reactant: C/C(N)=C/C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C(N)=C(\C#N)C1=CCN(Cc2ccccc2)CC1
Yield: 65.8 %

Procedure:
A solution of β-aminocrotononitrile (12 g, 147 mmol) and NEt3 (37 mL, 266 mmol) in CH2Cl2 (150 mL) was cooled with an ice bath to 0°. TiCl4 (7.9 mL, 72 mmol) in CH2Cl2 (100 mL) was added slowly with stirring followed by N-benzyl-4-piperidone (21.4 mL, 120 mmol) in one portion. The mixture was stirred for 24 h at ambient temperature and the volatiles were removed under reduced pressure. Ethly ether (400 mL) was added, and the resulting mixture was stirred vigorously until the residue was ground to a fine powder. The powder was filtered off and washed with ethyl ether (400 mL) and evaporation of the solvent afforded (E)-3-amino-2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-but-2-enenitrile as an oil (20 g, 70%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.S(=O)(=O)(O)O.C(Cl)(Cl)Cl>O>[Cl:1][C:2]1[C:17]2[C:10](=[O:12])[C:9]3[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1c2ccccc2oc2c([N+](=O)[O-])ccc(Cl)c12
Reaction time: 4.5 h

Procedure:
The 1-chloro-4-nitro-9H-xanthen-9-one was prepared as follows: Crude 2-(5'-chloro-2-nitrophenoxy)-benzoic acid (50 g) was added to 200 g of concentrated sulfuric acid. The mixture was held at 75° C. for 4.5 hours, and added to a stirred mixture of 1.5 1 of chloroform and water containing ice as needed to maintain the temperature below 35° C. The chloroform layer was separated, washed with 5% sodium bicarbonate, evaporated to dryness and the residue was crystallized from 200 ml of toluene and 30 ml of cyclohexane to provide the product mp 175°-186° C.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:44][N:45]([CH2:63][CH2:64][CH3:65])[C:46](=[O:62])[C:47]1[CH:48]=[C:49]([CH:53]=[C:54]([N:56]2[CH2:60][CH2:59][CH2:58][C:57]2=[O:61])[CH:55]=1)[C:50](O)=[O:51].[CH:66]12[CH2:72][CH:69]([CH2:70][CH2:71]1)[CH2:68][CH:67]2[NH:73][C:74](=[O:89])[C@H:75]([CH3:88])[CH2:76][C@H:77]([OH:87])[C@@H:78]([NH2:86])[CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:79]([C@H:78]([NH:86][C:50](=[O:51])[C:49]1[CH:53]=[C:54]([N:56]2[CH2:60][CH2:59][CH2:58][C:57]2=[O:61])[CH:55]=[C:47]([C:46]([N:45]([CH3:44])[CH2:63][CH2:64][CH3:65])=[O:62])[CH:48]=1)[C@@H:77]([OH:87])[CH2:76][C@H:75]([C:74](=[O:89])[NH:73][CH:67]1[CH2:68][CH:69]2[CH2:72][CH:66]1[CH2:71][CH2:70]2)[CH3:88])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E6, from N-methyl-5-(2-oxo-pyrrolidin-1-yl)-N-propyl-isophthalamic acid (D65) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:29]O)(=[O:28])[CH3:27]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:29][C:26](=[O:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-[2,5-bis(benzyloxy)phenyl]ethanone (2.25 g) and peracetic acid 40% (1.63 ml) in acetic acid (5.4 ml) was stirred at 60° C. for 1 h. After cooling to room temperature the precipitated product was collected by filtration, washed with cold ether and dried under reduced pressure. Acetic acid 2,5-bis(benzyloxy)phenyl ester was recrystallized from 2-propanol. Yield is 1.87 g. 1H NMR (DMSO-d6) 2.23 (s, 1H), 5.03 (s, 2H), 5.05 (s, 2H), 6.84-7.44 (m, 13H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]=2[N:11]=[CH:10][N:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Sc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CC(C)Sc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-isopropylthio-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 132°-134° C.) and piperazine.
Reaction SMILES: CC1C=CC(N)=C([N+]([O-])=O)C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](F)(F)F)=[CH:26][C:21]=2[N:20]=[C:19]1/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:27][C:25]1[CH:24]=[CH:23][C:22]2[N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[C:19](/[CH:31]=[CH:32]/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:20][C:21]=2[CH:26]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: Cc1ccc(N)c([N+](=O)[O-])c1
Product: Cc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-methyl-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57).
Reaction SMILES: [H-].[Na+].C([N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1)(=O)C.Br[CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:15]([N:10]1[C:9](=[O:13])[CH:8]=[N:7][NH:6][C:11]1=[O:12])[CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)n1ncc(=O)[nH]c1=O
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)cn[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a 50% sodium hydride suspension (4.8 g) in DMF (100 ml), compound 11a (15.5 g) dissolved in DMF (200 ml) is added drop by drop, maintaining the temperature at room temperature. After agitation for 2 hours, bromobutane (20 g) is added and the agitation continued for 12 hours. The reaction mixture is concentrated to dryness under vacuum at 60° C., taken up in water, and then extracted with methylene chloride. After concentration to dryness under vacuum, the oil is taken up in ethanol (100 ml), whereupon p-toluene-sulfonic acid (2 g) is added. After heating under reflux for 2 hours and leaving at room temperature for 12 hours, the reaction mixture is filtered. The precipitate is washed with an aqueous solution of sodium bicarbonate and water, and then dried in an oven under vacuum in order to give the compound 11b (8.7 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]2[C@@H:11]3[C@@H:16]([CH2:17][CH2:18][O:19][C:7]=2[CH:6]=1)[NH:15][CH2:14][CH2:13][O:12]3)[CH3:3].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:27][CH2:28][C:29]([N:15]1[CH2:14][CH2:13][O:12][C@@H:11]2[C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:2][CH3:3])=[CH:6][C:7]=3[O:19][CH2:18][CH2:17][C@@H:16]12)=[O:30]
Reactant: CCOc1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc2c(c1)OCC[C@@H]1[C@@H]2OCCN1C(=O)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.21 g of trans-3,4,4a,5,6,11b-hexahydro-9-ethoxy-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, prepared via an analogous procedure to the preceding Example, and 1.65 ml of triethylamine in 25 ml of methylene chloride is treated dropwise with a solution of 0.70 ml of chloroacetyl chloride dissolved in 10 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, washed with a dilute solution of hydrochloric acid, followed by a water wash, a wash of dilute sodium hydroxide solution and finally by a wash of a saturated solution of sodium chloride. The reaction mixture is dried over anhydrous magnesium sulfate and evaporated to dryness to obtain 1.44 g of trans-N-chloroacetyl-3,4,4a,5,6,11b-hexahydro-9-ethoxy-2H-[1]benzoxepino[5,4-b]-1,4-oxazine.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[CH2:20]([N:22]([CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:21]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:29][C:26]2[CH:25]=[CH:24][C:23]([N:22]([CH2:30][CH3:31])[CH2:20][CH3:21])=[CH:28][CH:27]=2)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(N=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])cc1
Yield: 83 %

Procedure:
To a refluxing, stirred suspension of 63.3 g (0.3 mole) of 6-nitroveratraldehyde and 1.0 ml glacial acetic acid in 800 ml ethanol was added over 15 min a solution containing 54 g (0.33 mole) of N,N-diethyl-p-phenylenediamine in 50 ml ethanol. The resulting solution was stirred and refluxed for 1 hr, then stored at 0°. The solid was collected, washed with 200 ml cold ethanol, and air dried to give 89 g (83%) of the product m.p. 117°-122°.
Reaction SMILES: [N+]([C:4]1C=C(C2C3N=CC=CC=3C(=O)NN=2)C=C[CH:9]=1)([O-])=O.[N+:21]([C:24]1[CH:25]=[C:26]([C:30]2[C:31]3[CH:40]=[CH:39][CH:38]=[N:37][C:32]=3[C:33](=[O:36])[NH:34][N:35]=2)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[C:26]([C:30]2[C:31]3[CH:40]=[CH:39][CH:38]=[N:37][C:32]=3[C:33](=[O:36])[N:34]([CH2:4][CH3:9])[N:35]=2)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)c2cccnc12
Product: CCn1nc(-c2cccc([N+](=O)[O-])c2)c2cccnc2c1=O

Procedure:
Following the procedures of Example 8A and substituting for 8-(3-nitrophenyl) pyrido[2,3-d]pyridazin-5-one with 5-(3-nitrophenyl)-pyrido[2,3-d]pyridazin-8-one there is obtained 5-(3-nitrophenyl)-7-ethylpyrido[2,3-d]pyridazin-8-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([NH:18][S:15]([CH3:14])(=[O:17])=[O:16])=[O:8])[CH:5]=1
Reactant: CS(N)(=O)=O
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of isophthalic acid monomethyl ester (500.0 mg, 2.8 mmol), methanesulfonamide (340 mg, 3.6 mmol) and DMAP (440 mg, 3.6 mmol) in anhydrous dichloromethane (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (690 mg, 3.6 mmol). The mixture was allowed to stir for 12 hours at room temperature and then concentrated under reduced pressure. The residue was chromatographed on a Biotage 40M eluting with 2% methanol/98% dichloromethane to provide the titled compound. MS (ESI) m/e 259 (M+H)+, 257 (M−H)−; 1H NMR (300 MHz, CD3OD) δ ppm 3.36 (s, 3H) 3.95 (s, 3H) 7.64 (t, J=7.80 Hz, 1H) 8.13 (dd, J=7.80, 1.36 Hz, 1H) 8.25 (m, 1H) 8.55 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.O.[NH2:19][NH2:20]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:19][NH2:20])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNc1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a suspension of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (5 g, 20 mmol) in 1-butanol (75 mL) was added hydrazine hydrate (2.0 ml, 40 mmol) at room temperature. The mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give the desired product. LCMS calculated for C10H14ClN6O (M+H): 269.1; found: 269.0.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:27][CH2:26][CH2:25]1
Reactant: C1CNC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC2)cn1
Yield: 28 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using azetidine instead of methylamine, to the title compound (32 mg, 28%) which was obtained as a light yellow oil. MS: m/e=350.3 [M+H]′.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[N:7][CH:8]=1.N[C:22]1C=NC(OC)=CN=1.ClC1C2C(=CC=CC=2)N=C(C)N=1>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:22])=[N:7][CH:8]=1
Reactant: COc1cnc(N)cn1
Reactant: COc1cnc(Nc2nc(C)nc3ccccc23)cn1
Agent: Cc1nc(Cl)c2ccccc2n1
Product: COc1cnc(N(C)c2nc(C)nc3ccccc23)cn1

Procedure:
(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The title compound was prepared from 2-amino-5-methoxy-pyrazine (105 mg, 0.84 mmol) and 4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol) by a procedure similar to Example 125c, yielding 106 mg of the title product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21](C)[N:20]=1>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]3([O:16][N:15]=[C:5]([C:4]#[C:3][C:22]4[CH:21]=[N:20][CH:19]=[CH:24][CH:23]=4)[CH2:14]3)[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1cccc(Br)n1
Reactant: C=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(C#Cc2cccnc2)=NO3)n1

Procedure:
The title compound was prepared following the procedure reported for the compound of Example 3, replacing 3-iodopyridine for 2-bromo-6-methylpyridine. After the usual work-up, the crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 7:3 to 3:7) affording the title product as yellow solid. Yield: 66.7%.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH:48]([OH:50])[CH3:49]>CN(C)C=O>[OH:50][CH:48]([CH3:49])[CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: CC(O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (129 mg, 0.25 mmol) (Example 22(a)) was dissolved in dimethylformamide. Sodium iodide (7.5 mg, 0.5 mmol), triethylamine (76 mg, 0.75 mmol) and 3-chloro-2-propanol (48 mg, 0.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 4 hours at ambient temperature, the temperature was then raised to 100° C. and kept there for 2 hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (2 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the organic phase and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (4 ml). The aqueous solution was washed with ether (5×2 ml). The aqueous solution was acidified, the water was evaporated, and the title compound was isolated as a hygroscopic white powder. Yield 75 mg (74%) The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([Br:11])=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCCC1>[Br:11][C:10]1[C:4]2[S:3][C:2]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:6][C:5]=2[C:7]([O:12][CH3:13])=[CH:8][CH:9]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Br)c2sc(Br)nc12
Solvent: C1CCOC1
Product: COc1ccc(Br)c2sc(N3CCOCC3)nc12
Temperature: 80 °C

Procedure:
A suspension of 2,7-dibromo-4-methoxybenzothiazole (1.8 g) and morpholine (10 ml) in tetrahydrofuran (10 ml) was heated at 80° C. for 2 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over magnesium sulphate (3 g), filtered and the filtrate evaporated in vacuo to yield an off white solid. This was purified by recrystallisation from ethyl acetatelhexane to yield the title compound as a white solid (1.2 g). TLC Rf 0.39 (50% ethyl acetate in hexane).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][S:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#CCSc1ccccc1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: ClC(Cl)Cl
Product: O=c1cc(CSc2ccccc2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-phenylsulfanyl-but-2-ynoic acid ethyl ester employing the procedure described in Example 94. [α]D25 −19.40 (c 0.5, CHCl3).