Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][NH:12][C:4]=2[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.S(C1C=CC(C)=CC=1)(O)(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[C:11]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[NH:12][C:4]=2[CH:3]=1
Reactant: N#Cc1nc(Cl)cc2[nH]cnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cc2[nH]c(C3CCCCO3)nc12
Temperature: 60 °C

Procedure:
6-Chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1 g) was dissolved in ethyl acetate (20 ml). To above solution was added 3,4-dihydro-2H-pyran (1 ml) and tosylic acid hydrate (50 mg). The mixture was heated at 60° C. for 10 hours, than washed with sodium bicarbonate (5%, 10 mL). The organic layer dried over sodium sulphate, solvent removed to give the title compound. 1H NMR (DMSO) □ 8.92 (s, 1H), 8.30 s, 1H), 5.81 (d, 1H), 4.00 (m, 1H), 3.78 (m, 1H), 2.18 (m, 1H), 2.07 (m, 1H), 1.67 (m, 4H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f7) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:5][C:4]=1[CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([O:19]C)=[O:18]>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:5][C:4]=1[CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCCC(CC(=O)OC)c1cc(C(=O)CC)c(OC)cc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)O)c1cc(C(=O)CC)c(OC)cc1OC

Procedure:
The methyl 3-(2,4-dimethoxy-5-propionylphenyl)octanoate prepared as described in step (i) above was hydrolyzed in a similar manner to that described in Preparation 7 to give the title compound as crystals, melting at 92.5-94° C. (from ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[SH:16].F[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[S:16][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1cc(S)c2cc(F)ccc2c1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Sc2cc(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 100 °C
Yield: 74.6 %

Procedure:
To a solution of (6-fluoro-4-mercapto-naphthalen-2-yl)-acetic acid (30 mg, 0.127 mmol) in N,N-dimethylformamide (2 mL), was added 1-fluoro-4-methanesulfonyl-benzene (43.4 mg, 0.25 mmol) and potassium carbonate (35 mg, 0.25 mmol) under a nitrogen atmosphere. After being heated under microwave conditions (100° C., 30 minutes), the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0-20% methanol in dichloromethane) to afford [6-fluoro-4-(4-methanesulfonyl-phenylsulfanyl)-naphthalen-2-yl]-acetic acid (37.0 mg, 74.6%) as an off-white powder. 1H NMR (400 MHz, CDCl3) δ ppm 7.86-7.93 (m, 4H), 7.69-7.74 (m, 2H), 7.34 (td, J=8.53, 2.65 Hz, 1H), 7.08-7.15 (m, 2H), 3.85 (s, 2H), 3.01 (s, 3H); MS cald. for C19H15FO4S2 390, obsd. (ESI+) [(M+H)+] 391.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=[C:5]2[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[N:29]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:31][C:24]=12.N#N>C1(C)C=CC=CC=1.[Cu]I.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>[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[N:29]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:30]([C:2]3[C:6]4=[N:7][C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=[C:5]4[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=3)=[CH:31][C:24]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(Cl)ccnc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc2c(nc1OC)c(Br)cn2C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 68.6 %

Procedure:
Bubble a solution of dimethoxyazaindole 11 (0.25 g, 0.70 mmol) and azaindole 26 (0.458 g, 0.77 mmol) in toluene (15 mL) with N2 for 15 min, then add CuI (14 mg, 0.07 mmol) and Pd(PPh3)4 (81 mg, 0.07 mmol) and agitate the mixture with the stream of N2 for 0.5 h, then heat at 120° C. under N2 for 20 h. Purification of the reaction mixture on SiO2 (flash chromatography, 40 g cartridge, elution with EtOAc at 10-30%/heptane) gives bisazaindole 27 (0.28 g, 68%) as a white solid: 1H NMR (CDCl3) δ 8.29 (d, 1H, J=5.4 Hz), 7.86 (s apparent overlapping d, 3H), 7.15 (m, 4H), 6.94 (s, 1H), 3.97 (s, 6H), 2.32 (s, 3H), 1.71 (s, 9H), TLC (EtOAc at 40%/heptane) Rf=0.40.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:16]([CH2:12][CH2:13][CH2:14][CH3:15])[C:17]2=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: CCCCN=C=O
Product: CCCCN1C(=O)CN(c2ccccc2)C1=O
Yield: 43.3 %

Procedure:
N-phenyl glycine (0.15 mole) was added with stirring over a 15 minute period to n-butyl isocyanate (0.15 mole). After the addition was complete the reaction mixture was refluxed for about 6 hours and then allowed to stand at room temperature until it solidified. The solidified mass was crystallized from ethanol and produced 0.065 moles of the above-described product having a melting point of 74° l C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:24]([Cu])#[N:25]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Yield: 24.9 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (0.91 g, prepared according to Arend et al. WO 2004108681) and CuCN (436 mg) in DMF (5 mL) was refluxed for 1 h; then cooled, diluted with DCM, filtered, then washed with water, dil. NaCl solution, dried over sodium sulphate, filtered, concentrated, the residue was column purified to give the desired product (195 mg). LC MS ESI: 337 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:37]=[C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:39][CH:40]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[S:39][CH:40]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2csc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-2-phenyl-1,3-thiazole (0.71 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.20 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:49]([O:51][CH2:52][CH3:53])=[O:50].C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:52]([O:51][C:49](=[O:50])[NH:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:3]=1)[CH3:53]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (20 mg, 0.037 mmol) in DCM (1 ml) was added pyridine (0.1 ml) followed by ethyl chloroformate (10.70 μl, 0.111 mmol). The vial was capped and the contents stirred at room temperature for 16 h. Un-reacted chloroformate was quenched by adding MP-Trisamine (91 mg, 0.186 mmol) and tumbling the vial for an additional 3 h. The resin was filtered and the volatiles removed in vacuo to afford crude (R)-ethyl(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate which was taken forward without purification. MS ESI calc'd. For C37H35N6O3 [M+H]+ 611. found 611.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[C:9](=[O:12])[CH2:10][Cl:11])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[BH4-].[Na+]>O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[C@@H:9]([OH:12])[CH2:10][Cl:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H](O)CCl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (R)-1-(2,5-difluorophenylmethyl)-3-chloro-2-oxopropylcarbamic acid tert-butyl ester (3.56 g, 11 mmol) in a solution of 9:1 THF:water (150 mL) at 0° C. is added NaBH4 (0.49 g, 13 mmol, 1.2 eq) and stirred for 5 min. The reaction mixture is concentrated under reduced pressure to a white solid which is suspended in a mixture of water and ethyl acetate. This biphasic mixture is cooled to 0° C. and quenched slowly with 2M NaHSO4 until pH˜2 and the layers rapidly separated. The organic layer is washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford a white solid as a mixture of diastereomers (3.5 g, 13 mmol, ˜5:2 R,R:R,S). The crude material was purified using General Purification Procedure C to afford the title compound as a single diastereomer of a white solid (2.2 g, 6.6 mmol).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([CH3:8])=O)#[N:2].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[C:6]([CH3:8])[CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH3:16]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)CCCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)CCCC#N
Reaction time: 10 h

Procedure:
A mixture of methyl 3-cyanopropyl ketone (55.5 g, 0.5 mole), ethyl cyanoacetate (56.5 g, 0.5 mole), acetic acid (6.0 g, 0.1 mole), ammonium acetate (3.85 g, 0.05 mole) and toluene (50 ml) was refluxed while azeotropically removing the water of reaction formed. After 10 hours the solution was vacuum distilled and a fraction (b.p. 145° C.-153° C., 0.5 torr) was collected. Total yield was 77.0 g or 74.7 percent. Analysis by infrared spectroscopy confirmed the product's identity as:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH:42][CH3:43]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH3:43])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CNCCOC
Product: COCCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and (2-methoxyethyl)methylamine according to conditions described in general procedure C. Mp: 81-82° C.; 1H NMR (400 MHz, CDCl3) δ 1.62-1.70 (m, 6 H), 3.06-3.40 (m, 14 H), 6.05 (s, 1 H), 6.76 (d, J=12.0 Hz, 1 H), 6.99 (d, J=7.8 Hz, 1 H), 7.26-7.30 (m, 2 H), 7.47-7.56 (m, 2 H), 7.88-7.96 (m, 3 H), 8.17 (s, 2 H).
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:20](=[O:29])[CH:19]=1)[C:12](OCC)=O)=[O:10]>CO>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:20](=[O:29])[CH:19]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1ccn(CCN(C)C)c(=O)c1
Agent: [Na]
Solvent: CO
Product: CN(C)CCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Yield: 39.6 %

Procedure:
To a stirred solution of sodium (2.94 g) in methanol (65 ml) was added nitroguanidine (11.81 g, containing 25% w/w water) and methanol (20 ml). The mixture was stirred at reflux for 60 minutes, and then a solution of ethyl α-formyl-β-(N-(2-dimethylaminoethyl)-2-oxo-4-pyridyl]propionate (25.05 g) in methanol (75 ml) was added dropwise over 90 minutes. The reaction mixture was stirred under reflux for a further 21 hours. The reaction mixture was evaporated under reduced pressure, dissolved in water (150 ml) and extracted with chloroform (3×35 ml). The combined chloroform extracts were washed with water (2×10 ml). The combined aqueous layer and aqueous washings were taken to pH 4 with glacial acetic acid. The solvent was then evaporated under reduced pressure and a solid by-product crystallised from ethanol. The mother liquors were evaporated and another crystallisation from ethanol gave a further solid by-product. The mother liquor was evaporated under reduced pressure to afford 2-nitroamino-5-[1-(2-dimethylaminoethyl)-2-oxopyridin-4-ylmethyl]pyrimidin-4-one (11.26 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])/[C:28](/[CH3:36])=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])/[C:28](/[CH3:36])=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: C/C(=C\c1ccccc1)C(=O)NCCN=[N+]=[N-]
Product: C/C(=C\c1ccccc1)C(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.1103 g, 0.397 mmol) was reacted with (E)-N-(2-azidoethyl)-2-methyl-3-phenylacrylamide (0.092 g, 0.397 mmol) following the general click procedure to give (E)-tert-butyl 2-amino-4-(5-(1-(2-(2-methyl-3-phenylacrylamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 7H), δ 6.94 (s, 2H), 6.06 (s, 2H), δ 4.46 (s, 2H), δ 3.79 (s, 2H), δ 2.61 (s, 2H), δ 2.27 (s, 2H0, δ 1.99 (s, 3H), δ 1.49 (bs, 11H), δ 1.18 (s, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 192.4, 191.3, 170.4, 150.9, 140.2, 136.2, 134.8, 131.6, 129.6, 128.6, 128.1, 122.1, 95.8, 85.2, 74.3, 53.7, 52.6, 50.7, 49.4, 40.1, 29.9, 29.3, 28.9, 28.2, 25.6, 14.4 ppm; HRMS (ESI) calcd for C27H37N7O3 (M+) 507.2958. found 507.2942, which was subsequently deprotected to give (E)-N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-methyl-3-phenylacrylamide hydrochloride (0.148 g, 84% yield). 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), δ 7.33 (s, 4H), δ 7.26 (s, 1H), δ 7.19 (s, 1H), δ 6.42 (s, 1H), δ 4.78 (s, 2H), δ 3.84 (s, 2H), δ 2.87 (s, 2H), δ 2.44 (s, 2H), δ 1.99 (s, 3H), δ 1.76 (s, 2H), δ 1.59 (s, 2H), δ 1.42 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 174.7, 136.0, 134.4, 131.5, 129.3, 128.7, 128.3, 128.0, 127.6, 108.6, 94.6, 53.1, 39.2, 27.6, 27.9, 27.7, 27.6, 24.1, 23.8, 23.1, 14.3, 13.4 ppm; HRMS (ESI) calcd for C22H29N7O (M+) 407.2434. found 407.2429.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[CH3:9][N:10]([CH3:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[CH3:9][N:10]([CH3:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NCCc1cccs1
Solvent: CCO
Product: CN(C)c1ccc(C=NCCc2cccs2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
2-(2-Thienyl)-ethylamine (5 g, 39.4 mmol), 4-dimethylaminobenzaldehyde (5.9 g, 94 mmol) triethylamine (6 ml) and ethanol (150 ml) were mixed at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated to 75 ml by evaporation in vacuo and the solid formed was filtered and dried to afford 6.82 g (67%) dimethyl-{4-[(2-thiophen-2-yl-ethylimino)-methyl]-phenyl}-amine.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[C:6]1([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:18]1([C:13]2[C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:23]=[CH:22][C:21]([S:1]([OH:5])(=[O:4])=[O:3])([S:1]([OH:3])(=[O:5])=[O:4])[CH2:20][CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(-c2ccccc2-c2ccccc2)cc1
Solvent: O
Product: O=S(=O)(O)C1(S(=O)(=O)O)C=CC(c2ccccc2-c2ccccc2)=CC1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
880 g of concentrated sulfuric acid were heated to 110° C, and 270.5 g of terphenyl were added. The temperature was raised to 140° C and left on that level for 4 hours. After cooling down to 100° C, 800 ml of water were added dropwise, and the mixture was allowed to cool and then filtered with suction, giving a crude product which was used direct in the next stage. Purity (HPLC): 99.7%; yield: 565 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH3:21]>[Pd]>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:21]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2ccccc2)cc1C)C(=O)OC
Agent: [Pd]
Product: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 46 b], (2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to give (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]1([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3([CH3:30])[CH3:29])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)nc23)C(C)(C)C1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
To a solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (170 mg, 0.617 mmol) and (R)-tert-butyl 4-amino-3,3-dimethylpiperidine-1-carboxylate (144 mg, 0.633 mmol) in DMF (1543 μl) was added DIEA (237 μl, 1.358 mmol). The reaction was heated at 90° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate (100 ml). The ethyl acetate layer was washed with water (3×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was purified via flash chromatography (ISCO silica gel column, 0-10% MeOH-DCM) to afford (R)-tert-butyl 4-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (255 mg, 0.546 mmol, 88% yield) as a faint yellow solid. ESI-MS (analytical LCMS Method A): m/z 467.0 ([M+H]+). HPLC (analytical HPLC Method A) Rt: 3.413 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C:6](=[CH2:10])[C:7]([OH:9])=[O:8].[C:14]([OH:17])(=[S:16])[CH3:15]>>[C:14]([S:16][CH2:10][CH:6]([CH2:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([Br:1])[CH:3]=1)[C:7]([OH:9])=[O:8])(=[O:17])[CH3:15]
Reactant: CC(O)=S
Reactant: C=C(Cc1cccc(Br)c1)C(=O)O
Product: CC(=O)SCC(Cc1cccc(Br)c1)C(=O)O
Temperature: 50 °C
Yield: 95 %

Procedure:
To a 5 ml pear-shaped flask containing 2-(3-bromobenzyl)acrylic acid (0.44 g, 1.83 mmol) was added thioacetic acid (1 ml, 1.065 g, 13.99 mmol). The mixture was heated at 50° C. for 2.5 hours, after which excess thioacetic acid was removed under reduced pressure. The residue was co-evaporated with toluene twice, then purified via silica gel column chromatography eluting with 0 to 2% MeOH in CH2Cl2, giving 2-(acetylsulfanylmethyl)-3-(3-bromophenyl)propionic acid as a colorless glue, 0.55 g, 95% yield, HPLC purity: 96.9%.