Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([C:27]5[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=5)[CH2:35]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Fc1ccc(C2CNCCN2)cc1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccc(F)cc5)C4)cc3nc21
Yield: 42.3 %

Procedure:
The reaction is performed under the conditions of Example 4, but starting with 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8 ]-naphthyridine-3-carboxylic acid (1.5 g) and (RS)-2-(4-fluorophenyl)piperazine (3.4 g) in pyridine (15 cc). (RS)-1-Ethyl-7-fluoro-4-oxo-8-[3-(4-fluorophenyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.92 g) is obtained in the form of a yellow solid, m.p. 298° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1)[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.Cl.Cl[CH2:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:14][N:13]1[C:9]([C:3](=[N:2][O:1][CH2:17][C:18]2[N:19]=[C:20]([NH2:23])[S:21][CH:22]=2)[C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)=[CH:10][N:11]=[CH:12]1
Reactant: Nc1nc(CCl)cs1
Reactant: Cn1cncc1C(=NO)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1cncc1C(=NOCc1csc(N)n1)c1cccs1
Temperature: 25 °C
Reaction time: 51 h
Yield: 24.5 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(2-thienyl)methanimine (4.08 g, 19.7 mmol) and 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (4.01 g, 21.7 mmol) in acetonitrile (50 mL) were added cesium carbonate (13.5 g, 41.4 mmol) and potassium iodide (327 mg, 1.97 mmol). After stirring at room temperature for 51 h, potassium iodide (5.90 g, 35.5 mmol) was added and the mixture was stirred for 72 h at room temperature then at 70° C. for 3.5 h. The reaction mixture was filtered, the insolubles washed with acetone and methanol, and the filtrate concentrated in vacuo, diluted in ethyl acetate (50 mL), washed with water (2×30 mL), dried over MgSO4 and concentrated to dryness in vacuo. Purification of the residue on silica gel afforded 4-[({[(1-methyl-1H-imidazol-5-yl)(2-thienyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine [1.54 g, yield 23%; HPLC/MS: m/z=320 (M+H); log P(HCOOH)=0.22].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.FC(F)(F)C(O)=O.[NH2:21][C@H:22]1[CH2:26][CH2:25][C@@H:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:21][C@H:22]2[CH2:26][CH2:25][C@@H:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)[C@@H]1CC[C@H](N)C1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 90 °C
Reaction time: 1.67 h
Yield: 53.2 %

Procedure:
To a stirred mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.18 g, 0.84 mmol) and ethyl (1R,3S)-3-aminocyclopentanecarboxylate trifluoroacetate (0.25 g, 0.92 mmol) in isopropyl alcohol (2.3 mL) was added N,N-diisopropylethylamine (0.73 mL, 4.2 mmol). The resulting mixture was stirred at 90° C. for 100 min, and then the solvent was evaporated. The crude residue was purified on silica gel, eluted with 10-60% EtOAc in hexanes to give 0.15 g (55%) of the desired product. LCMS calculated for C15H18N3O4S (M+H)+: m/z=336.1. Found: 336.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([O:53][CH3:54])[C:50]=1[O:51][CH3:52])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:32]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([O:42]C)=[O:41])[C:31]4[CH:44]=[CH:45][CH:46]=[CH:47][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].O.[OH-].[Li+].[CH3:58][S:59]([OH:62])(=[O:61])=[O:60].C(OCC)C>O1CCCC1.O>[CH3:58][S:59]([OH:62])(=[O:61])=[O:60].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([O:53][CH3:54])[C:50]=1[O:51][CH3:52])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([NH:27][C:28]3[N:32]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([OH:42])=[O:41])[C:31]4[CH:44]=[CH:45][CH:46]=[CH:47][C:30]=4[N:29]=3)[CH2:25][CH2:26]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COC(=O)c1ccccc1Cn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Agent: CS(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccccc4C(=O)O)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-methoxycarbonylbenzyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (0.6 g, 0.8 mmol) and lithium hydroxide hydrate (0.11 g, 2.4 mmol) in tetrahydrofuran (24 mL) and water (8 mL). After 18 hours, evaporate the reaction mixture in vacuo to remove the tetrahydrofuran to obtain a solid. Collect the solid and add tetrahydrofuran (40 mL). Add a solution of methanesulfonic acid (0.24 g, 2.6 mmol) in tetrahydrofuran (3 mL). Add diethyl ether (200 mL) to give a residue. Decant the supernatant, add diethyl ether, and stir to give a solid. Collect the solid and dry in vacuo to give the title compound: mp; 161-175° C.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:22][C:23]([O-:25])=O)[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:27])C1C=CC=CC=1.[Li+].C(Cl)CCl.C1C=[CH:44][C:45]2N(O)N=[N:48][C:46]=2C=1>C(Cl)(Cl)Cl.C(N)C#C.[Hg](OC(C)=O)OC(C)=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:26]([C:10]2[N:11]=[C:12]3[C:19]([CH3:21])([CH3:20])[N:18]([CH2:22][C:23]4[O:25][C:45]([CH3:44])=[CH:46][N:48]=4)[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[OH:8])=[O:27])=[CH:31][CH:32]=1
Reactant: CC1(C)c2nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c(=O)n2CCN1CC(=O)[O-]
Reactant: On1nnc2ccccc21
Agent: C#CCN
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [Li+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Cc1cnc(CN2CCn3c(nc(C(=O)NCc4ccc(F)cc4)c(O)c3=O)C2(C)C)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of lithium (3-(benzyloxy)-2-{[(4-fluorobenzyl)amino]carbonyl}-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidin-8-yl)acetate (1 eq.) in CHCl3, propargylamine (1.1), EDC (2 eq.) and HOBt (2 eq.) were added and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was taken up in EtOAc, washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting crude was directly dissolved in acetic acid and Hg(OAc)2 (0.1 eq.) was added. The mixture was heated at 100° C. overnight and was then concentrated under reduced pressure. The residue was directly purified by RP-HPLC and after lyophilisation of the desired fractions, the O-benzyl protected material was dissolved in MeOH and stirred 1 hour under an H2 atmosphere in the presence of 10% Pd/C. The catalyst was then filtered off through celite, the filtrate was concentrated under reduced pressure and then the residue was dissolved in MeCN and H2O and lyophilized to afford the titled oxazole. 1H-NMR (400 MHz, d6-DMSO) δ 12.17 (br. s, 1H), 9.43 (t, J=6.2 Hz, 1H), 7.37 (dd, J=8.1 Hz, J=5.7 Hz, 2H), 7.17 (t, J=8.9 Hz, 2H), 6.77 (s, 1H), 4.47 (d, J=6.2 Hz, 2H), 3.80 (s, 2H), 3.71 (t, J=5.0 Hz, 2H), 3.00 (t, J=5.1 Hz, 2H), 2.27 (s, 3H), 1.53 (s, 6H); MS (ES) C22H24FN5O4 requires 441. Found: 442 (M+H+).
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.ClC1C=C([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C(C4C=CC(I)=CC=4)C4N(C)C(S)=NN=4)[CH:24]=3)[N:19]3[N:41]=[N:42][N:43]=[C:18]3[N:17]=2)C=CC=1.CCOC(C)=O>O.C1COCC1>[N:41]1[N:19]2[C:20]3[C:25]([CH:16]=[N:17][C:18]2=[N:43][N:42]=1)=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: Cn1c(S)nnc1C(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)cnc1nnnn12
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 140.2 %

Procedure:
Sodium nitrite (0.0005 mol) was added at 5° C. to a solution of nitric acid (1 ml) in water (1 ml) A solution of 5-[[5-(3-chlorophenyl)tetrazolo[1,5-a]quinazolin-7-yl](4-iodophenyl)methyl]-4-methyl-4H-1,2,4-triazole-3-thiol (0.0005 mol), obtained in stage a), in THF (2 ml) was added dropwise. The mixture was stirred at 5° C. for 15 minutes and poured out into ice water. EtOAc was added. The mixture was washed with potassium carbonate 10%. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.23 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1;15–40 μm). The pure fractions were collected and the solvent was evaporated., yielding 0.12 g (44%) of tetrazolo[1,5-a]quinazoline, 5-(3-chlorophenyl)-7-[(4-iodophenyl)(4methyl-4H-1,2,4-triazol-3-yl)methyl]-, mp. 150° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8]C(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)[CH2:4][CH:5]([CH3:7])[CH3:6].[CH:26]1([CH2:31][O:32][C:33]2[N:38]=[C:37]([C:39]([OH:41])=O)[CH:36]=[N:35][C:34]=2[N:42]2[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.N[C@H](CO)CC(C)C>>[OH:1][CH2:2][C@@H:3]([NH:8][C:39]([C:37]1[CH:36]=[N:35][C:34]([N:42]2[CH2:43][CH2:44][C:45]([F:48])([F:49])[CH2:46][CH2:47]2)=[C:33]([O:32][CH2:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[N:38]=1)=[O:41])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: O=C(O)c1cnc(N2CCC(F)(F)CC2)c(OCC2CCCC2)n1
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Agent: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1cnc(N2CCC(F)(F)CC2)c(OCC2CCCC2)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-cyclopentylmethoxy-5-(4,4-difluoro-piperidin-1-yl)-pyrazine-2-carboxylic acid and (S)-leucinol (commercially available). m/z (ES+): 441.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][C:20](=O)[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.C(N(CC)CC)C.C(O)(=O)C.Cl.[NH2:38][C@@H:39]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42]C(C)(C)C)=[O:41]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][CH:20]([NH:38][C@H:39]([C:40]([OH:42])=[O:41])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(=O)CC3)cc12
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(N[C@H](C(=O)O)C(C)(C)C)CC3)cc12
Reaction time: 8 h

Procedure:
To a mixture of Example 83B (100 mg, 0.296 mmol), triethylamine (0.091 mL, 0.652 mmol), and acetic acid (0.085 mL, 1.482 mmol) in dichloromethane (3 mL) was added (S)-tert-butyl 2-amino-3,3-dimethylbutanoate hydrochloride (133 mg, 0.593 mmol) and MP-(CN)BH3 resin (Biotage, 2.17 mmol/g, 546 mg, 1.186 mmol). The reaction mixture was shaken on an orbital shaker overnight. The reaction mixture was diluted with 5 mL dichloromethane and the resin filtered off, rinsing with dichloromethane and methanol. The crude material was purified via column chromatography: Analogix Intelliflash™ 280, 12 g silica cartridge, 0-4% methanol/dichloromethane gradient over 30 minutes. The material was dissolved in 5 mL dichloromethane and treated with excess trifluoroacetic acid and stirred at room temperature overnight. The volatiles were removed in vacuo, the residue was dissolved in 5 mL methanol, and the mixture was treated with excess 2 M HCl/diethyl ether. The solution was stirred at room temperature for 20 minutes and then diluted with diethyl ether. The resultant solid was collected by filtration and dried under high vacuum to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H) 8.80-9.10 (m, 3H) 8.36 (s, 1H) 7.46-7.57 (m, 2H) 7.27-7.39 (m, 1H) 6.60-6.78 (m, 2H) 4.02 (d, J=10.07 Hz, 1H) 3.76-3.88 (m, 3H) 3.51-3.61 (m, 1H) 3.15-3.36 (m, 2H) 2.57-2.93 (m, 2H) 2.34 (s, 1H) 1.99-2.16 (m, 1H) 1.78-1.98 (m, 1H) 1.15 (s, 9H). MS (ESI+) m/z 453.2 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=1[NH:26][C:27](=[O:45])[CH2:28][CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]2[O:41][CH2:42][CH2:43][O:44][C:36]=12)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH3:17])([CH3:16])[CH3:15].O>O1CCCC1.CN(C)C=O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:11]2[C:10](=[O:12])[CH2:9][CH2:8][C:7]2=[O:13])=[CH:20][C:19]=1[NH:26][C:27](=[O:45])[CH2:28][CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]2[O:41][CH2:42][CH2:43][O:44][C:36]=12)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C1CCC(=O)N1
Reactant: CCCCCC(CC(=O)Nc1cc(CBr)ccc1C(C)(C)C)c1cccc2c1OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(CC(=O)Nc1cc(CN2C(=O)CCC2=O)ccc1C(C)(C)C)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
2 ml (2.00 mmol) of a 1M potassium t-butoxide solution in tetrahydrofuran were added to a solution of 200 mg (2.02 mmol) of succinimide in 10 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 15 minutes. A solution of 680 mg (1.35 mmol) of N-[2-t-butyl-5-bromomethylphenyl]-3-(2,3-ethylenedioxyphenyl)octanamide (prepared as described in Preparation 70E) in 5 ml of dimethylformamide was then added to the mixture. The mixture was stirred at room temperature for 1 hour, after which water was added, and the aqueous mixture was extracted with diethyl ether. The extract was washed with 10% v/v aqueous hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate and a with saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 565 mg of the title compound as a colorless foam-like substance in a 80% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][C:24]([Cl:27])=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:12]=2)=[C:5]([NH2:7])[N:6]=1.C1([Li])C=CC=CC=1.[CH3:35][N:36]=[C:37]=[O:38].C(O)(=O)C>C1COCC1.CO.CN1CCCC1=O>[NH2:7][C:5]1[N:6]=[C:2]([NH:1][C:37]([NH:36][CH3:35])=[O:38])[S:3][C:4]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([NH:19][C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)[N:12]=1
Reactant: Nc1nc(N)c(-c2nc(-c3cccc(NC(=O)c4ccc(Cl)s4)c3)cs2)s1
Reactant: CN=C=O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CNC(=O)Nc1nc(N)c(-c2nc(-c3cccc(NC(=O)c4ccc(Cl)s4)c3)cs2)s1
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A solution of N-[3-(2′,4′-diamino-[2,5′]bithiazolyl-4-yl)phenyl]-5-chloro-thiophene-2-carboxamide (0.2307 mmol) (prepared as in Example E(3)), dissolved in anhydrous THF (5.0 mL) and anhydrous N-methylpyrolidinone (1.0 mL) at −78° C., was treated phenyllithium (0.2307 mmol), followed by methylisocyanate (0.3461 mmol). After 5 minutes a second portion of phenyllithium (0.2307 mmol) was added slowly. After stirring for an additional 15 minutes, the reaction was quenched with acetic acid (0.6921 mmol), and methanol (0.5 mL), concentrated, and purified by reverse phase HPLC. The major component was collected, dissolved in ethyl acetate, extracted with NaHCO3, brine, dried over MgSO4, concentrated until a precipitate formed, and filtered. Mass of the resulting light-yellow powder after drying under high vacuum was 46 mg (41% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:9]2[C@@H:8]([NH2:12])[CH2:7][CH2:6][C:5]=2[N:4]=1.[CH:13]1([C:16]2[C:24]3[C:19](=[N:20][C:21]([O:28][CH2:29][C:30](O)=[O:31])=[CH:22][C:23]=3[CH:25]([F:27])[F:26])[N:18]([CH3:33])[N:17]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:13]1([C:16]2[C:24]3[C:19](=[N:20][C:21]([O:28][CH2:29][C:30]([NH:12][C@@H:8]4[C:9]5[C:5](=[N:4][C:3]([CH3:2])=[CH:11][CH:10]=5)[CH2:6][CH2:7]4)=[O:31])=[CH:22][C:23]=3[CH:25]([F:26])[F:27])[N:18]([CH3:33])[N:17]=2)[CH2:14][CH2:15]1
Reactant: Cn1nc(C2CC2)c2c(C(F)F)cc(OCC(=O)O)nc21
Reactant: Cc1ccc2c(n1)CC[C@@H]2N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(n1)CC[C@@H]2NC(=O)COc1cc(C(F)F)c2c(C3CC3)nn(C)c2n1
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To the solution of (S)-2-methyl-6,7-dihydro-5H-[1]pyrindin-5-ylamine hydrochloride (75 mg, 0.41 mmol) and (3-cyclopropyl-4-difluoromethyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (building block A2, 110 mg, 0.37 mmol) in DMF (6 ml) were added DIPEA (0.26 ml, 1.48 mmol) and HATU (169 mg, 0.44 mmol) and the reaction was stirred at it for 3 h. The mixture was diluted with EtOAc, washed with aqueous bicarbonate solution and brine, dried over sodium sulfate, and the solvents were evaporated under reduced pressure. Purification by preparative HPLC (Gilson GX-281, Waters Sunfire C18, 5 μm, 30×100 mm with guard column 19×10 mm, solvent A: water with 0.1% TFA, solvent B: acetonitrile, gradient 10-30% B in 16 min, flow rate 50 ml/min) gave the title compound as off-white solid (115 mg, 72%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.61 (d, 1H), 7.47 (t, 1H), 7.36 (d, 1H), 6.99 (d, 1H), 6.93 (s, 1H), 5.32 (dd, 1H), 4.89 (s, 2H), 3.81 (s, 3H), 3.34 (s, 3H), 2.93-2.89 (m, 1H), 2.86-2.80 (m, 1H), 2.41 (s, 3H), 2.41-2.36 (m, 1H), 2.24-2.19 (m, 1H), 1.92-1.86 (m, 1H), 0.94-0.87 (m, 4H); LCMS RtI=3.032 min; [M+H]+=428.2]
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.C1(C)C=CC=CC=1>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)c1cn2cc(-c3ccccc3)ccc2n1
Yield: 65.2 %

Procedure:
0.391 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 0.237 g of phenylboronic acid, 45 mg of tetrakis(triphenylphosphine)palladium, 4 ml of 2M aqueous sodium carbonate solution, 6 ml of acetonitrile and 6 ml of toluene are charged to a microwave tube. The mixture is heated for 20 minutes in the microwave device adjusted to 150° C. After cooling, the organic phase is separated, dried and evaporated. The residue is taken up in a mixture of dichloromethane and pentane. The solid is filtered off and then purified by triturating from methanol to give 0.22 g of N,6-diphenylimidazo[1,2-a]pyridine-2-carboxamide in the form of an ecru solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([O:9][CH3:10])[CH:8]=1)#[N:2].C(N(CC)CC)C.[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22].C(OCC)(=O)C>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][S:21]([C:20]([F:26])([F:25])[F:19])(=[O:23])=[O:22])=[C:7]([O:9][CH3:10])[CH:8]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1O
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C#N)ccc1OS(=O)(=O)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 5-cyano-2-hydroxyanisole (600 mg, mmol) and triethylamine (1.40 mL, 10.0 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under argon atomosphere. Trifluoromethanesulfonyl chloride (642 μL, 6.03 mmol) were added thereto at −10° C., and stirred at the same temperature for 1 hour. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (979 mg) as a colorless solid. (Yield 87%)
Reaction SMILES: C[N:2]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][N:8](C)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1CCCNCCNCCCNCC1.CN1CCCN(C)CCN(C)CCCN(C)CC1.CC1CC(C)(C)NCCNC(C)CC(C)(C)NCCN1.CN1CCCNCCN(C)CCCNCC1.C(N1CCCNCCN(CC)CCCNCC1)C.CN1CCN2CCN(CCN(C)CCC2)CCC1.C(N1CCN2CCN(CCN(CC)CCC2)CCC1)C.C(N1CCN2CCN(CCN(C)CCC2)CCC1)CCCCCCC>>[NH:2]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CN1CCNCCN(C)CCNCC1
Agent: C1CNCCNCCCNCCNC1
Agent: CC1CC(C)(C)NCCNC(C)CC(C)(C)NCCN1
Agent: CCCCCCCCN1CCCN2CCN(C)CCCN(CC1)CC2
Product: C1CNCCNCCNCCN1

Procedure:
1,7-dimethyl-1,4,7,10-tetraazacyclododecane; 1,4,8,11-tetraazacyclotetradecane (cyclam); 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane; 5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane; 1,8-dimethyl-1,4,8,11-tetraazacyclotetradecane; 1,8-diethyl-1,4,8,11-tetraazacyclotetradecane (diethylcyclam); 5,12-dimethyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane (dimethyl-Bcyclam), 5,12-diethyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane (diethyl-Bcyclam) and 5-N-octyl-12-methyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]([N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(N(CC)CC)C>ClCCl>[CH:12]([CH:13]([N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:11]
Reactant: CN(C(CO)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C(C=O)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Yield: 93.4 %

Procedure:
Oxalyl cloride (0.51 g, 4.00 mmol) and dimethyl sulfoxide (0.63 g, 8.01 mmol) were dissolved in dichloromethane (10 ml) and the solution was cooled to −78° C. To the solution, a solution of (±)-1-hydroxymethyl-N-methyl-N-(4-phenoxybenzene-sulfonyl)-2-phthalimidoethylamine (1.70 g, 3.64 mmol), the product of (5) above, in dichloromethane (25 ml) was added dropwise with stirring and this was stirred for 30 minutes. Triethylamine (1.84 g, 18.2 mmol) was added dropwise to the mixture and this was stirred at room temperature for 2 hours. To the reaction mixture, ice-water was added and then this was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound (1.58 g, yield 93%) as a white amorphous solid.