Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([OH:16])=O)[CH:8]=2)[NH:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[CH:42]=[C:43]([NH:48]/[C:49](/[NH2:52])=[N:50]/O)[CH:44]=[CH:45][C:46]=1[Cl:47].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([NH:48][C:49]2[N:52]=[C:14]([CH2:13][O:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:11][CH2:10]4)[O:16][N:50]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: O=C(O)COc1ccc2c(c1)CCC(=O)N2
Reactant: N/C(=N\O)Nc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1CCc2cc(OCc3nc(Nc4ccc(Cl)c(Cl)c4)no3)ccc2N1
Temperature: 110 °C
Yield: 3.4 %

Procedure:
To a stirred solution of 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetic acid (0.15 g, 0.67 mmol) were added HOBt (0.1 g, 0.74 mmol), EDC (0.15 g, 0.74 mmol) and DIPEA (0.22 g, 1.69 mmol). The resulting reaction mixture was stirred at room temperature for 30 min. (E)-1-(3,4-dichlorophenyl)-2-hydroxyguanidine (0.15 g, 0.67 mmol) in DMF was added to the above reaction mixture followed by sodium sulfate (0.48 g, 3.39 mmol) and the reaction mixture was heated at 110° C. for 12 h. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated. Purification was by preparative HPLC to give 6-((3-(3,4-dichlorophenylamino)-1,2,4-oxadiazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (9.3 mg, 7%). 1HNMR: 400 MHz, DMSO-d6: δ 2.42 (q, J=7.20 Hz, 2H), 2.85 (t, J=7.60 Hz, 2H), 5.41 (s, 2H), 6.78-6.87 (m, 2H), 6.94 (d, J=2.40 Hz, 1H), 7.41 (dd, J=2.80, 8.80 Hz, 1H), 7.59 (d, J=8.80 Hz, 1H), 7.71 (d, J=2.80 Hz, 1H), 9.96 (s, 1H), 10.39 (s, 1H). LCMS, RT 1.880 min; LCMS (ES-API), m/z 405.1.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=O)[CH:4]=O.[CH2:9]([NH:16][CH2:17][CH2:18][NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH3-]C#N.[Na+].[OH-].[Na+]>CN(C=O)C>[CH2:9]([N:16]1[CH2:17][CH2:18][NH:19][CH:3]([C:2]([F:8])([F:7])[F:1])[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCNCc1ccccc1
Reactant: O=CC(=O)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
A solution of 3,3,3-trifluoro-2-oxopropanal (0.31 g, 2.3 mmol; Intermediate 43) in DMF (10 mL) was cooled to 0° C. and a solution of N-benzylethane-1,2-diamine (0.37 g, 2.72 mmol) in DMF (10 mL) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was redissolved in THF (5 mL) and citrate buffer (5.3 mL; 0.4 M), followed by NaBH3CN (0.31 g, 4.9 mmol), were added. The resulting mixture was stirred at room temperature overnight. The mixture was made basic (pH 8) with aqueous NaOH (8 mL; 1 M) and the aqueous layer was extracted twice with DCM (15 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by LC-MS prep to give 1-benzyl-3-(trifluoromethyl)piperazine (66 mg, 12%). HPLC 94%, RT=1.25 min (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, CDCl3) δ ppm 2.77 (s, 2H) 3.17-3.31 (m, 1H) 3.32-3.64 (m, 3H) 3.83-4.02 (m, 1H) 4.13-4.31 (m, 2H) 6.68 (s, 1H) 7.30-7.55 (m, 5H). MS (ESI+) m/z 245. *Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[CH:6][CH:7]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:14][O:12][C:11]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([CH2:8][O:9][CH3:10])[N:4]=1)=[O:13]
Reactant: COCc1ccc(Br)c(C(=O)O)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COCc1ccc(Br)c(C(=O)OC)n1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 3-bromo-6-methoxymethyl-pyridine-2-carboxylic acid (200 mg, 0.81 mmol) in benzene (4 ml) and MeOH (1 ml) was slowly added trimethylsilyl-diazomethane (0.41 ml, 0.81 mmol) at ambient temperature, and the reaction mixture was stirred for 2 hours. The solvents were removed and the residue was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using an ethyl acetate/hexane eluent to yield 158 mg (75%) of the title compound as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9](Cl)[CH:10]=1)[C:5]([O-:7])=[O:6].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:10]=1)[C:5]([O:7][CH3:21])=[O:6]
Reactant: Nc1cc(Cl)cc(C(=O)[O-])c1[N+](=O)[O-]
Reactant: C1COCCN1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of 3-amino-5-chloro-2-nitrobenzoate (71; 3.3 g, 14.35 mmol) in DMF (66 ml) was added morpholine (48; 7.12 g, 81.78 mmol) and K2CO3 (11.28 g, 81.78 mmol). The resulting reaction mixture was stirred at 105° C. for 4 h. It was then filtered, diluted with water (500 ml), and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Column chromatography afforded methyl 3-amino-5-morpholino-2-nitrobenzoate 72 (2.1 g, 52.1%) as a brown yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O1CCOCC1.[ClH:37]>C(O)(C(F)(F)F)=O.CO>[ClH:37].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[C:4]=23)[CH2:18]1
Reactant: COCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: COCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Yield: 55 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate was stirred in TFA (3 mL) for 30 minutes, and then the reaction was concentrated to dryness. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 12M column, 0-50% CH3CN/water gradient; 20 CV) to yield a solid. The solid was dissolved in a minimal amount of methanol and was added dropwise to a 4N HCl dioxane solution. The resulting solid was collected, rinsed with DCM and dried under high vacuum to yield (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo [2,3-b]pyridin-3-yl)-2-methoxyacetamide hydrochloride (22 mg, 55%) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.78 (d, 1H), 9.85 (s, 1H), 8.32 (br s, 3H), 8.27 (s, 1H), 7.93 (s, 1H), 4.09 (q, 2H), 3.68-3.58 (m, 1H), 3.53-3.38 (m, 3H), 3.49 (s, 3H), 3.32-3.26 (m, 1H), 3.02-2.96 (m, 1H), 2.24-2.18 (m, 1H), 1.92-1.82 (m, 2H), 1.56-1.46 (m, 1H); LCMS (APCI+) m/z 365, 382 (M)+, Retention time=1.89 minutes (Method 1).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C-:13]#[N:14].[K+]>ClCCl>[CH2:1]([C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: OCc1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#CCc1ccccc1
Temperature: 52.5 °C
Yield: 195.4 %

Procedure:
To a solution of 40.00 g (180 mmoles) of benzyl alcohol in. 530 ml of dichloromethane was added within 5 min 32.7 ml (450 mmoles) of thionyl chloride. The solution was evaporated in vacuo to dryness, which was repeated after toluene addition: 46.30 g (106.9%) of crude benzyl chloride, which was dissolved in 230 ml of dimethylformamide and treated with 23.50 g (360 mmoles) of potassium cyanide. The mixture was heated for 4 hours to 50-55° C. The salt was filtered off and the filtrate evaporated in vacuo to dryness, which was repeated after the addition of water, the residue was taken up in ether and extracted with 1N NaOL. The ether phase is evaporated to dryness to yield 41.20 g (99.0%) of crude benzyl cyanide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3N)=[N:9][C:5]=2[CH:4]=1.Cl.N([O-])=O.[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: c1ccncc1
Reactant: COc1ccc(N)c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccccn2)c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1

Procedure:
The product of step (b) above (500 mg) was treated with concentrated hydrochloric acid (0.8 ml) and water (0.8 ml) to form a paste. The paste was stirred at 0°-10° and a solution of sodium nitrite (105 mg) in water (0.5 ml) added dropwise. After stirring for 40 minutes the resultant solution was added slowly to pyridine (5 ml) stirred at 80°. The mixture was stirred for a further 40 minutes then concentrated in vacuo. The residue was slurried with 0.880 ammonia and the mixture again concentrated in vacuo. The residue was slurried with water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated to leave a brown gum. Flash chromatography produced the required product as a pale brown solid, MS MW 393 bp 216.
Reaction SMILES: [CH3:1][N:2](C=O)C.CI.CN(C)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[C-]#N.[K+]>O.C1COCC1>[N+:20]([C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH2:10][C:1]#[N:2])=[CH:12][NH:13]2)=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: CN(C)Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Yield: 36 %

Procedure:
To a mixture of DMF (35 mL) and MeI (74.6 g, 0.53 mol) in water (35 mL) and THF (400 mL) was added dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine (23 g, 0.105 mol). After the reaction mixture was refluxed for 10 min, potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was kept refluxing overnight. The mixture was then cooled to room temperature and filtered. The filtrate was washed with brine (300 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (7.5 g, 36%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[N:9]=[C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][NH:15]C(OC(C)(C)C)=O)=[O:13])[CH:7]=[CH:6][C:5]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.C(O)CCC.CC(OC)(C)C>CO>[ClH:1].[ClH:1].[CH3:2][O:3][C:4]1[N:9]=[C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][NH2:15])=[O:13])[CH:7]=[CH:6][C:5]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1nc(/C=C/C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CO
Solvent: CCCCO
Product: COc1nc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Conc. HCl (5.85 mL) was added to the suspension of tert-Butyl 2-{(2E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]prop-2-enoyl}hydrazinecarboxylate (1.17 g, 3.13 mmol) in methanol (5.85 mL) with an ice-bath cooling. The reaction mixture was stirred at room temperature for 30 minutes. 1-Butanol (5.85 mL) and MTBE (5.85 mL) were added to the reaction mixture, and the mixture was stirred for 20 minutes with an ice-bath cooling. The mixture was filtrated, and the residue was washed with 1-butanol-MTBE (2:8) (5.85 mL) and dried under the reduced pressure to obtain the title compound (937 mg, 78.2% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]([N:20]([CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C(=O)OC(C)(C)C)[CH2:18][OH:19])=[CH:14][CH:13]=1)=[O:10].N1C=CC=CC=1.[CH3:47][S:48](Cl)(=[O:50])=[O:49].[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>ClCCCl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[OH:19][CH2:18][C@@H:17]([NH:20][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16][C:15]1[CH:39]=[CH:40][C:12]([NH:11][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:48]([CH3:47])(=[O:50])=[O:49])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)[C@H](CO)Cc1ccc(NC(=O)Nc2ccccc2N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1NC(=O)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl N-[(1S)-1-[4-[[[(2-aminophenyl)amino]carbonyl]amino]benzyl]-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (20.0 mg) in 1,2-dichloroethane (200 μl) were added successively 1.0 M solution of pyridine in 1,2-dichloroethane (54.5 μl) and 1.0 M solution of methanesulfonyl chloride in 1,2-dichloroethane (43.6 μl) at room temperature. After stirring for 2 hours, the solvent was removed by evaporation and the residue was purified by a recycling preparative high pressure liquid chromatography equipped with a gel permeation chromatography column (eluent: chloroform) to give a light brown solid. The solid was dissolved in 1,2-dichloroethane (200 μl). To the solution was added trifluoroacetic acid (200 μl) and the mixture was stirred for 30 minutes. The solvent was removed by evaporation to give N-[2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]-carbonyl]amino]phenyl]methanesulfonamide trifluoroacetate (20.3 mg) as a light brown solid.
Reaction SMILES: Cl.Cl.COC(=O)[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.Cl[C:56]([C:58]1[CH:59]=[C:60]([O:64]C(=O)C)[CH:61]=[CH:62][CH:63]=1)=[O:57].[C:68]([O-:71])(O)=[O:69].[Na+]>CCOC(C)=O>[CH:48]1([CH2:47][O:46][C:43]2[CH:42]=[CH:41][C:40]([C@H:38]3[CH2:37][O:36][C:32]4=[CH:33][C:34]5[CH2:35][C@@H:26]([C:24]([NH:23][C@@H:6]([CH2:7][C:8]6[CH:9]=[CH:10][C:11]([O:14][C:15]7[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=7[CH3:22])=[CH:12][CH:13]=6)[C:68]([OH:71])=[O:69])=[O:25])[N:27]([C:56](=[O:57])[C:58]6[CH:63]=[CH:62][CH:61]=[C:60]([OH:64])[CH:59]=6)[CH2:28][C:29]=5[CH:30]=[C:31]4[O:39]3)=[CH:45][CH:44]=2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Reactant: O=C([O-])O
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3cccc(O)c3)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride and excess acetic acid 3-chlorocarbonyl-phenyl ester were reacted in a biphasic mixture of EtOAc and saturated aqueous NaHCO3. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z) 813.
Reaction SMILES: ClC1C=C(Cl)N=C(C2C=CC=CC=2)N=1.Cl[C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:17]=1.[CH2:31]([CH:33]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:34][OH:35])[CH3:32]>CC(C)CCO>[Cl:22][C:20]1[CH:21]=[C:16]([O:35][CH2:34][CH:33]([CH2:31][CH3:32])[CH2:36][CH2:37][CH2:38][CH3:39])[N:17]=[C:18]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:19]=1
Reactant: Cc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1
Reactant: CCCCC(CC)CO
Agent: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CC(C)CCO
Product: CCCCC(CC)COc1cc(Cl)nc(Sc2ccc(C)cc2)n1
Yield: 85 %

Procedure:
The preparation is carried out analogously to the method described in Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-(p-methylphenylthio)pyrimidine and 3-methylbutanol by 2-ethylhexanol. The title compound is obtained as a resin in a yield of 85% of theory.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:6]1[CH:10]=[C:9]([NH:11][C:12]([CH:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[N:8]=[CH:7]1)C.[OH-:34].[K+].CO.O>C(OCC)(=O)C>[CH2:27]([CH:5]([N:6]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2([OH:34])[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[N:8]=[CH:7]1)[C:4]([OH:3])=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)C2c3ccccc3-c3ccccc32)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCCCCCC(C(=O)O)n1cnc(NC(=O)C2(O)c3ccccc3-c3ccccc32)c1
Yield: 18.1 %

Procedure:
When 2.1 g of α-hexyl-4-[(9H-fluoren-9-ylcarbonyl)amino]-1H-imidazole-1-acetic acid ethyl ester was heated with 3.0 g of potassium hydroxide, 30 ml of methanol, and 15 ml of water at reflux for one hour, upon adjustment of pH to 3.8, a thick oil formed. The oil was dissolved in ethyl acetate and separated from the aqueous layer. The organic layer was dried and concentrated in vacuo. The oil was taken up in ethanol and saturated with hydrogen chloride gas. The resulting product was purified by high pressure liquid chromatography to provide 0.370 g of the titled product, m.p. 128° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=1[C:22]#[N:23].CCN(C(C)C)C(C)C>CC#N>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:20]([CH2:19][N:9]([CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[C:21]([CH:24]=1)[C:22]#[N:23]
Reactant: Cc1cccnc1CNC(C)c1ccccn1
Reactant: COc1ccc(CBr)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(C#N)c1

Procedure:
Using General Procedure A: Reaction of (3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amine, 2-bromomethyl-5-methoxybenzonitrile (Ando, K. et al. Bull. Chem. Soc. Jpn. 1980, 53, 2885-2890), DIPEA and KI in CH3CN gave 5-methoxy-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-benzonitrile as an orange oil. 1H NMR (CDCl3) δ 1.60 (d, 3H, J=6.9 Hz), 2.08 (s, 3H), 3.73 (d, 1H, J=15.0 Hz), 3.74 (d, 1H, J=12.3 Hz), 3.78 (s, 3H), 3.92 (d 1H, J=12.3 Hz), 3.93 (d, 1H, J=15.0 Hz), 4.03 (q, 1H, J=6.9 Hz), 6.95-7.04 (m, 3H), 7.16 (ddd, 1H, J=7.5, 5.0, 1.0 Hz), 7.29 (t, 2H, J=6.6 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.65 (td, 1H, J=7.7, 1.8 Hz), 8.32 (dd, 1H, J=4.8, 1.2 Hz), 8.58 (dd, 1H, J=4.8, 0.9 Hz).
Reaction SMILES: [CH:1]1([C:6]([CH2:8][C:9]2[C:10]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[C:11]3[C:15](=[C:16]([CH3:20])[C:17]=2[CH2:18][CH3:19])[CH2:14][O:13][C:12]3=[O:21])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Si:23]([O:22][C:10]1[C:9]([CH2:8][C@@H:6]([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=2)[OH:7])=[C:17]([CH2:18][CH3:19])[C:16]([CH3:20])=[C:15]2[C:11]=1[C:12](=[O:21])[O:13][CH2:14]2)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC(=O)C1CCCC1)C(=O)OC2
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C[C@H](O)C1=CCCC1)C(=O)OC2
Temperature: -30 °C
Reaction time: 16 h

Procedure:
Cyclopentyl (4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl methyl)methanone (4.2 g) was treated with a 1M toluene solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole (3 ml). The toluene was evaporated in vacuo and methylene chloride added (2 ml). The reaction mixture was cooled to -30° C. and borane/dimethyl sulfide (0.33 ml) was added three times at 45 minute intervals. The reaction mixture was stirred 16 hours at -30° C. and quenched by addition of 1M hydrogen chloride/ether (3 ml). Toluene was added (10 ml) and the solution filtered, diluted with ether (200 ml), washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. Drying and evaporation gave an oil which was purified by silica gel chromatography to give (S)-2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-1-cyclopentenyl-1-hydroxyethane. Further purification by crystallization from t-butylmethyl ether gave material with an enantiomeric excess of 97.8% (Chiracel OD-H, 85:15 hexane:i-propanol, 0.8 ml/minute, minor 8.3 minutes, major 9.2 minutes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.Br[C:12]1[C:13]2[N:14]([C:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[O:23])=[CH:20][N:21]=2)[N:15]=[C:16](Cl)[CH:17]=1.ClC1C=C(Cl)C2N(C(C(NC3C=CN=CC=3)=O)=CN=2)N=1.[C@H:51]1([NH2:58])[CH2:56][CH2:55][C@H:54]([NH2:57])[CH2:53][CH2:52]1>O1CCCC1>[NH2:57][C@H:54]1[CH2:55][CH2:56][C@H:51]([NH:58][C:16]2[CH:17]=[C:12]([NH:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]3[N:14]([C:19]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[O:23])=[CH:20][N:21]=3)[N:15]=2)[CH2:52][CH2:53]1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Br)cc(Cl)nn12
Reactant: COc1ccc(CN)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C(Nc1ccncc1)c1cnc2c(Cl)cc(Cl)nn12
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
(4-methoxyphenyl)methanamine (0.050 mL, 0.383 mmol) was added to a suspension of a mixture of 8-bromo-6-chloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and a 6,8-dichloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 1E (0.118 g, 0.383 mmol) in tetrahydrofuran (1.0 mL) in a 2 dram screw vial equipped with a stir bar and a teflon coated screw cap. The mixture was heated at 80° C. overnight. The reaction was cooled to room temperature. The reaction was concentrated to dryness under a stream of nitrogen. (trans)-Cyclohexane-1,4-diamine (0.437 g, 3.83 mmol) was added and the mixture was heated to 160° C. After 2 h, the reaction was partitioned between dichloromethane (1.5 mL) and water (1.5 mL). The dichloromethane was removed and concentrated under a stream of nitrogen to provide 6-((trans)-4-aminocyclohexylamino)-8-(4-methoxybenzylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.103 g).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[C:10]1(=[O:20])[O:15][C:13](=O)[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)CCCCCCCCCCC>[CH3:1][C:2]1[C:3]2[O:4][C:8]3[C:2]([CH3:1])=[C:3]([OH:4])[CH:5]=[CH:6][C:7]=3[C:13]3([O:15][C:10](=[O:20])[C:11]4[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:5]=2[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1c(O)cccc1O
Agent: CCCCCCCCCCCC(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: Cc1c(O)ccc2c1Oc1c(ccc(O)c1C)C21OC(=O)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture comprising 62 g of 2-methylresorcinol, 30 g of phthalic anhydride, 2 g of potassium hydrogen sulfate and 500 ml of ethyl laurate is brought to 200° C. for 3 hours. After cooling, the crude product is filtered and washed with acetone and then dried. The product obtained is a dark orange powder.