Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[NH2:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]([CH3:29])[CH3:28].C(N(CC)CC)C>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:25]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:17][CH:18]=1
Reactant: CN(C)CC(=O)NN
Reactant: CCOC(N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Temperature: 75 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methaneamine hydrochloride (200 mg, 0.62 mmol), N-amino-2-(dimethylamino)acetamide (147.5 mg, 0.95 mmol), and molecular sieves in ethanol was added triethylamine (0.25 mL, 1.86 mmol). The reaction was allowed to stir under a nitrogen atmosphere at 75° C. overnight. The reaction was filtered using a fritted funnel and the filtrate was concentrated. This was purified by semi-preprative HPLC. The material was taken up in ethyl acetate and washed with aqueous sodium bicarbonate. This organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (192 mg, 23% yield). 1H NMR (CD3OD) δ 8.7 (s, 1H), 8.0–8.1 (m, 3H), 7.7 (d, 1H), 7.25 (t, 2H), 4.5 (s, 2H), 3.0 (s, 6H), ES-MS (m/z) 337 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (320 mg, 1.16 mmol) [prepared according to the procedure of Example 168], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (318 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (535 mg, 1.14 mmol) in Chloroform (9.5 mL). DIEA (840 μl, 4.81 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (106 mg, 0.16 mmol, 17%): LC-MS (ES) m/z=557 (M+H)+.
Reaction SMILES: [Br-].[CH3:2][Si:3]([CH3:29])([CH3:28])[C:4]#[C:5]/[CH:6]=[CH:7]/[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.C(=O)=O.[CH:38]([C@H:40]1[O:44][C:43]2([CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[O:42][C@H:41]1[CH2:50][O:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=O>C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:2][Si:3]([CH3:29])([CH3:28])[C:4]#[C:5]/[CH:6]=[CH:7]/[CH:8]=[CH:38]\[C@H:40]1[O:44][C:43]2([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]2)[O:42][C@H:41]1[CH2:50][O:51][CH2:52][C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54]
Reactant: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1C=O
Reactant: C[Si](C)(C)C#C/C=C/C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1/C=C\C=C\C#C[Si](C)(C)C
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
A slurry of 2E-5-trimethylsilylpent-2-en-4-ynyltriphenyl-phosphonium bromide, a compound of formula (Q), (67.1 g, 0.14 mol) in THF (875 mL) was stirred under nitrogen, cooled in a dry ice acetonitrile bath (−30° C. internal), and treated with a solution of n-butyllithium (66.5 mL, 0.133 mol, 2M in hexane) via dropwise addition. The dry ice bath was replaced with an ice bath and the reaction was stirred for about 15 minutes until a homogeneous, red-colored mixture was obtained. The dry ice bath was replaced and the reaction mixture was cooled to about −30° C. The reaction mixture was treated with a solution of 1,1-dimethylethyl [[(2S,3S) 3-formyl-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate (40 g, 0.127 mol) in 125 mL of THF. The reaction mixture was stirred for 1 hour with the dry ice bath. With the internal temperature around −30° C., the reaction mixture was diluted with saturated potassium phosphate (pH=5). The aqueous layer was washed with ether (3×). Combined organic layers were washed with water and brine, dried, treated with silica gel, and concentrated. The residue was diluted with about 3:1 mixture of hexane to ethyl acetate to precipitate the impurities. The resulting slurry was filtered and the solid was washed with the hexane/ethyl acetate mixture. The filtrate was concentrated. The procedure was repeated using a mixture of ether and hexane (1:1) and treatment with silica gel to give 50.29 g of 1,1-dimethylethyl [[(2S,3R)-3-[(1Z,3E)-6-(trimethylsilyl)-1,3-hexadien-5-ynyl]-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate as an oil. Proton NMR analysis of the product indicated a 2:1 mixture of E,Z- to E,E-isomers. The data for the for the Z,E isomer can be extracted from the mixture: 1H NMR (CDCl3) δ 0.15 (s, 9H), 1.3 (m, 2H), 1.4 (s, 9H), 1.6 (m, 8H), 3.45 (m, 2H), 3.92 (m, 2H), 4.34 (m, 1H), 5.02 (m, 1H), 5.48 (dd, 1H), 5.6 (d, 1H), 6.16 (dd, 1H), 6.82 (dd, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[N:38]=[CH:37][N:36]=[C:35]([O:39][C:40]2[C:45]3[N:46]=[C:47]([NH:49][C:50](=[O:52])[CH3:51])[S:48][C:44]=3[CH:43]=[CH:42][CH:41]=2)[CH:34]=1>>[C:50]([NH:49][C:47]1[S:48][C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([O:39][C:35]3[N:36]=[CH:37][N:38]=[C:33]([C:24]4[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:30])[F:31])=[CH:28][C:23]=4[NH:22][C:19]([C@@H:9]4[CH2:10][CH2:11][C@H:12]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:8]4[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:20])[CH:34]=3)[C:45]=2[N:46]=1)(=[O:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4C(=O)OC(C)(C)C)ncn3)cccc2s1

Procedure:
(2S,5R)-1-(tert-Butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid (350 mg, 1.2 mmol, Neosystem-T) was reacted with N-(4-(6-(2-amino-4-(trifluoromethyl)-phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (446 mg, 1.0 mmol, prepared as described in WO04014871) under the conditions of Example 45(a) to give the title compound as a white solid. MS (ESI, neg. ion.) m/z: 719 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O-:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[K+].CN(C=O)C.Br[CH2:22][CH2:23][CH2:24][CH2:25][O:26][N+:27]([O-:29])=[O:28]>C(Cl)Cl>[N+:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][O:11][C:10](=[O:12])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1)([O-:29])=[O:28]
Reactant: COc1cc(/C=C/C(=O)[O-])ccc1O
Reactant: O=[N+]([O-])OCCCCBr
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)OCCCCO[N+](=O)[O-])ccc1O
Temperature: 40 °C
Yield: 70 %

Procedure:
A mixture of potassium (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate (2.07 g; 9 mmol), obtained in the previous step, DMF (8.3 g), KI (0.5 g) and a 20% w/w solution (82.5 g) of 4-bromobutylnitrate (16.5 g; 16.7 mmol) in CH2Cl2 is heated under stirring to 40° C. and kept at this temperature under stirring for 136 h. After work up, (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-(nitrooxy)butyl ester was obtained in 70% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:22]([C:25]3[C:33]4[O:32][C:31]([F:35])([F:34])[O:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])C)[CH:17]=[CH:16][C:15]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>CCOCC.ClCCl>[ClH:38].[CH3:37][O:36][C:15]1[CH:16]=[CH:17][C:18]([NH:20][S:22]([C:25]2[C:33]3[O:32][C:31]([F:35])([F:34])[O:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCNCC1

Procedure:
The title compound was prepared by treatment of 4-{5-[(2,2-Difluoro-benzo[1,3]dioxole-4-sulfonyl)-methyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester with HCl in ether and dichloromethane as solvent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:25]1([NH2:32])[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>CS(C)=O>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:32][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(CNc2nc(-c3cc(F)ncc3Cl)ccc2F)c1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3ccc(F)c(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
5′-chloro-2′,5-difluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (0.022 g, 0.063 mmol) was dissolved in anhydrous DMSO (0.93 mL) and charged to a microwave vial, and then treated with trans-cyclohexane-1,4-diamine (0.072 g, 0.629 mmol). The reaction mixture then was heated at 100° C. for 18 hr. The material was purified by preparative reverse-phase HPLC to yield 0.0151 g (44%) of N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine as the TFA salt. LCMS (m/z): 444.2 (MH+), retention time=0.7 min.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=1.[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:45])[CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:38]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25]>O1CCOCC1.C(OCC)(=O)C>[CH3:23][S:24]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:34]=[C:35]([NH:45][C:13]3[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=3)[CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:38]=2)[CH2:31][CH2:32]1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)N1CCN(c2cc(N)cc(-c3ccccc3)c2)CC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(c2cc(Nc3nccc(C(F)(F)F)n3)cc(-c3ccccc3)c2)CC1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
p-Toluenesulfonic acid (21.46 mg, 0.113 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (22.5 mg, 0.123 mmol) were added to a solution of 5-[4-(methylsulfonyl)piperazin-1-yl]biphenyl-3-amine (34 mg, 0.103 mmol) in dioxane (1 mL) and the reaction mixture was stirred for 14 hours at 100° C., then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL), then washed with saturated aqueous NaHCO3 (30 mL) followed by brine (30 mL). The aqueous layers were extracted with ethyl acetate (30 mL), then the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided N-{5-[4-(methylsulfonyl)piperazin-1-yl]biphenyl-3-yl}-4-(trifluoromethyl)pyrimidin-2-amine MS ESI calc'd. for C22H23F3N5O2S [M+H]+ 478, found 478. 1H NMR (400 MHz, Acetone): δ 9.18 (s, 1H); 8.82 (d, J=4.9 Hz, 1H); 7.71-7.66 (m, 4H); 7.47 (t, J=7.5 Hz, 2H); 7.37 (t, J=7.3 Hz, 1H); 7.23 (d, J=4.9 Hz, 1H); 7.02 (s, 1H); 3.43 (d, J=10.6 Hz, 8H); 2.91 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:47].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:47])[NH2:41])=[CH:36][CH:35]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCn1c(COc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCCn1c(COc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 1e from 1-(3-ethoxycarbonylpropyl)-2-[(4-cyanophenyl)-oxymethyl]-5-(quinoline-8-sulphonylamino)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl>CN(C)C1C=CC=CC=1>[C:1]([NH:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(N)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Acetyl chloride (13 ml) was added dropwise to a solution of 2.98 g of ethyl 3-amino-2-nitrobenzoate and 20 ml of N,N-dimethylaniline in an ice bath. The mixture was stirred at room temperature for 48 hours. The reaction solution was acidified with 10% hydrochloric acid, and was extracted twice with ethyl acetate. The organic layer was washed three times with water. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized with hexane. The crystals were separated through filtration, washed with hexane, and dried to give 3.30 g of ethyl 3-acetylamino-2-nitrobenzoate.
Reaction SMILES: C(OC([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH:34]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)([CH3:35])[CH3:36]
Reactant: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2cc(-c3cnc(NC(C)C)s3)cc(-c3ccccc3)c2n1
Yield: 83.1 %

Procedure:
A solution of ethyl 6-(2-(tert-butoxycarbonyl-(isopropyl)amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (75 mg) in 4 ml of TFA was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane (50-100%) as eluent to give 50 mg of ethyl 6-(2-(isopropylamino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate as a light yellow solid. LCMS (Conditions C): 2.90 min (RT); (M+H)+=407.33 (100%). 1H NMR, 400 MHz, CDCl3: δ 8.25 (s, 1 H), 8.16 (m, 1 H), 8.02 (m, 2 H), 7.52-7.43 (m, 3 H), 7.37 (d, 1H), 7.29 (s, 1H), 4.44 (q, J=7.1 Hz, 2 H), 3.60 (m, 1 H), 1.42 (m, 9 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: [H][H]
Reactant: Cc1nc2c(N)nc3cnccc3c2n1CC(C)C
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CC(C)C)CCNC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.1 g, 0.4 mol) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated, and the aqueous layer was extracted three times with dichloromethane (100 mL). The combined dichloromethane extracts were dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene to provide 6,7,8,9-tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p., 226-230°C. Analysis: Calculated for C14H21N5+1.75 H2O: %C, 57.81; %H, 8.49; %N, 24.07; Found: %C, 57.89; %H, 8.04; %N, 23.45.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[NH2:16][C:17]1[C:22]2[O:23][CH2:24][O:25][C:21]=2[C:20]([C:26]#[C:27][CH2:28][O:29][CH2:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:19][C:18]=1[Cl:35].Cl[C:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH3:50])=[C:44]([O:47][CH3:48])[CH:45]=2)[N:40]=[CH:39][N:38]=1>CN(C=O)C.[Cl-].[NH4+]>[Cl:35][C:18]1[CH:19]=[C:20]([C:26]#[C:27][CH2:28][O:29][CH2:30][C:31]([NH:33][CH3:34])=[O:32])[C:21]2[O:25][CH2:24][O:23][C:22]=2[C:17]=1[NH:16][C:37]1[C:46]2[C:41](=[CH:42][C:43]([O:49][CH3:50])=[C:44]([O:47][CH3:48])[CH:45]=2)[N:40]=[CH:39][N:38]=1
Reactant: CNC(=O)COCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OC)c(OC)cc23)c2c1OCO2
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 39.3 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.23 ml) in tetrahydrofuran (1.0M, 1.23 mmol) was added over 5 min. to a stirred mixture of 2-{[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]oxy}-N-methylacetamide (0.182 g) and 4chloro-6,7-dimethoxyquinazoline (0.125 g) in DMF (6.0 ml) cooled to 0° C. under a nitrogen atmosphere; the mixture was stirred for 1.25 hr at ambient temperature. The reaction mixture was diluted with saturated aqueous ammonium chloride (60 ml) and extracted with ethyl acetate (3×30 ml). The organic extracts were washed with brine (30 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methanol and dichloromethane as eluent. There was thus obtained the title compound as a solid (0.106 g). NMR Spectrum: (DMSOd6) 2.62 (d, 3H), 3.91 (s, 6H), 3.98 (s, 2H), 4.50 (s, 2H), 6.15 (s, 2H), 7.15 (s, 1H), 7.17 (s, 1H), 7.76 (s, 1H), 7.80 (s, 1H), 8.31 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 485 and 487.
Reaction SMILES: CCNC=C(CC)C(=CCCCCC)CCC.C=CC=C.[CH2:22]([C:24]1([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:35][CH:34]=[CH:33][CH2:32][CH2:31][CH:30]=[CH:29][CH2:28][CH:27]([CH:36]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:37][CH3:38])[N:26]=[CH:25]1)[CH3:23]>>[CH2:43]([C:24]1([CH2:22][CH3:23])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH:36]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:37][CH3:38])[N:26]=[CH:25]1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCCC(CC)C1CC=CCCC=CCC(CC)(CCCC)C=N1
Agent: C=CC=C
Agent: CCCCCC=C(CCC)C(=CNCC)CC
Product: CCCCC(CC)C1CCCCCCCCC(CC)(CCCC)C=N1

Procedure:
Reaction of N-2-ethyl-hexylidene-(2-ethylhexen-1-ylamine) [produced by reaction of 2-ethylcaproaldehyde with ammonia] with 1,3-butadiene to 3-ethyl-3-n-butyl-12-(3-heptyl)-1-aza-1,5,9-cyclododecatriene (7:3 isomeric mixture; b.p. 106°-109° C./13 Pa; nD20 =1.4895), and hydrogenation to obtain 3-n-butyl-3-ethyl-12-(3-heptyl)-1-azacyclododecene; b.p. 130° C./4 Pa.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH:17]2[O:21][C:20]3[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:28])=[C:25]([OH:26])[C:19]=3[CH:18]2[CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5](=[O:8])[O:6]C.[OH-].[Na+].O>C1COCC1>[O:1]=[C:2]([C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][CH:17]2[O:21][C:20]3[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:28])=[C:25]([OH:26])[C:19]=3[CH:18]2[CH2:30][CH2:31][CH3:32])=[CH:13][CH:14]=1)[CH2:3][CH2:4][C:5]([OH:8])=[O:6]
Reactant: CCCC1c2c(ccc(C(C)=O)c2O)OC1CSc1ccc(C(=O)CCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1c2c(ccc(C(C)=O)c2O)OC1CSc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 18 (430 mg, 0.9418 mmoles) was taken up in THF (5.8 ml) to which was added 1N NaOH (2.4 ml) and 2.5 ml H2O. The reaction mixture was stirred at room temperature under N2. After two hours, the THF was removed in vacuo and the reaction mixture was diluted to twice its volume with H2O and extracted with CHCl3. The aqueous phase was acidified with conc. HCl, extracted into CHCl3 and the organic phase was dried and concentrated. The residue was triturated with ether to afford the title compound, m.p. 110°-112°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[N:16]=[C:15]([CH3:22])[CH:14]=1>C(O)C>[CH3:22][C:15]1[CH:14]=[C:13]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[N:16]=1
Reactant: Cc1cc(Cl)n2ccnc2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2ccnc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
4-(trifluoromethyl)aniline (602 mg, 3.74 mmol) was added to the stirred solution of 5-chloro-7-methylimidazo[1,2-a]pyrimidine (522 mg, 3.12 mmol) in excess of absolute ethanol. The reaction mixture was heated intermittently to maintain homogeneity (clear) of the reaction mixture. After stirring overnight at room temperature, the excess ethanol was removed in vacuo and the resultant crude was purified using column chromatography. Yield 0.593 mg (65% yield).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:25][OH:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1>ClCCl.[O-2].[Mn+4].[O-2]>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:25]=[O:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:23])([F:22])[F:24])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1

Procedure:
To a solution of 1 g of [[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol in 7 ml of dichloromethane was added 2.35 g of manganese(IV)oxide (activated with charcoal). The resulting mixture was heated under reflux for four hours. The cooled reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (heptane 80/ethyl acetate 20) to give 0.53 g of 2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazole-5-carbaldehyde.