Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1)(=[O:28])=[O:27]>>[CH2:38]([O:37][C:35]([CH:31]1[CH2:30][N:29]([S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:27])=[O:28])[CH2:34][CH2:33][N:32]1[C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:36])[CH3:39]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 9 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl 1-(2-naphthylsulphonyl)piperazine-3-carboxylate to give 2-ethoxycarbonyl-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine as a glassy solid in 9% yield;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([NH:16][OH:17])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.CN(C=O)C.C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([N:16]([OH:17])[C:25]([NH2:24])=[O:26])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ON[C@@H]1COc2cc(OCc3ccccc3)ccc21
Agent: C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)N(O)[C@@H]1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a 5 L, 3-necked flask equipped with a mechanical stirrer, thermometer and condenser with CaCl2 drying tube was added under a N2 atmosphere (S)-N-[6-benzyloxy-2,3-dihydrobenzofuran-3-yl]hydroxylamine (129.0 g, 0.501 mol) in THF (2.6 L). The resulting mixture was stirred at room temperature for 0.5 h, at which time was added in one portion, trimethylsilylisocyanate (107.2 mL, 86.6 g, 0.752 mol). The mixture was then heated at reflux for 15 min, then was cooled to 5° C. with an ice bath. The precipitate which formed was collected by filtration to afford a white solid. A second crop of peach-colored solid was obtained from concentration of the filtrate. This was taken up in a minimum of DMF, heated and treated with Darco. Filtration and cooling afforded a white solid which was collected, dried and combined with the first crop. The combined solids were dissolved in EtOH (20 vol), heated to reflux, cooled, collected and dried to afford the title compound (105.4 g, 70.2%); m.p. 192.5°-193° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22]([O-])(=[O:24])C.[Na+]>CN(C)C=O.O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:22]=[O:24])=[C:8]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)[O-]
Reactant: Cn1c(-c2ccccc2)cc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(-c2ccccc2)c(C=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 150 ml of dimethylformamide 46 ml of phosphorus oxychloride were added dropwise care being taken that the temperature of the reaction mixture did not rise above 20°C. Subsequently to the obtained mixture 103.5 g of 1-methyl-2-phenylindole dissolved in 200 ml of dimethylformamide were added dropwise. During the addition the temperature of the reaction mixture was kept in the range of 20° to 40°C and thereupon for 1 hour between 40° and 45°C. Then the reaction mixture was poured into a solution of 490 g of sodium acetate dissolved in 500 ml of water to which 500 g of ice were added. The precipitated aldehyde was separated by suction, washed with water and methanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:36][CH2:37][CH3:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]([CH2:37][CH3:38])[C:26](=[O:27])[CH2:25][N:14]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [CH2:1]([C:5]1[CH:61]=[CH:60][C:8]([CH2:9][N:10]([C:18]2[CH:19]=[C:20]([CH:38]=[C:39]([N:41](C(OC(C)(C)C)=O)[CH2:42][C:43]3[CH:48]=[CH:47][C:46]([CH2:49][CH:50]([CH3:52])[CH3:51])=[CH:45][CH:44]=3)[CH:40]=2)[C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:24]=2)=[O:22])C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[ClH:62].CCCCCC>C1(C)C=CC=CC=1.O1CCOCC1>[ClH:62].[ClH:62].[CH2:49]([C:46]1[CH:45]=[CH:44][C:43]([CH2:42][NH:41][C:39]2[CH:38]=[C:20]([CH:19]=[C:18]([NH:10][CH2:9][C:8]3[CH:60]=[CH:61][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)[CH:40]=2)[C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:24]=2)=[O:22])=[CH:48][CH:47]=1)[CH:50]([CH3:52])[CH3:51]
Reactant: CC(C)Cc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)c2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(CNc2cc(NCc3ccc(CC(C)C)cc3)cc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-[3-[3,5-bis[N-(4-isobutylbenzyl)-N-tert-butoxycarbonylamino]benzoyl]indol-1-yl]butyric acid (1.02 g) in toluene (10 ml) was added 4N solution of hydrogen chloride in 1,4-dioxane (30 ml) at 25° C. The mixture was stirred at 25° for 1 hour, and then hexane (30 ml) was added. The precipitates were filtered and washed with isopropyl ether and hexane to give 4-[3-[3,5-bis[(4-isobutylbenzyl)amino]benzoyl]indol-1-yl]butyric acid dihydrochloride (688 mg) as white powder.
Reaction SMILES: CN(C)C(=O)C.[Br:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=2)=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[Br:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:19]([O:21][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:20])=[CH:17][N:18]=2)=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cnc(-c2ccc(Br)nc2)[nH]1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)c1cnc(-c2ccc(Br)nc2)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
To an N,N-dimethylacetamide solution containing 2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylic acid (4.99 g) and diisopropylethylamine (4.21 mL) was added benzyl bromide (3.81 g) under ice-cooling, after stirring the mixture for 5 minutes, the temperature of the mixture was raised to room temperature and the mixture was stirred overnight. Water was added to the reaction mixture under ice-cooling, and the precipitated solid was collected by filtration, washed with water and n-hexane, and dried to obtain benzyl 2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylate (6.01 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[O:30]1[CH2:35][CH2:34]OCC1>>[C:5]([NH:7][CH2:34][CH2:35][O:30][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])(=[O:6])[CH3:4]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1COCCO1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCCNC(C)=O)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and N-acetylethiazolamine in dioxane. ES-MS m/e (%): 472 (M+H+, 100).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:28])[CH:25]=[C:24]([CH3:26])[C:23]2[C:10](=[CH:11][CH:12]=[C:13]3[C:22]=2[C:21](=[O:27])[O:20][C:19]2[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:9]1.C(OCC)(=O)C.Cl>O1CCCC1.O>[OH:27][CH2:21][C:22]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[OH:20])=[CH:12][CH:11]=[C:10]2[C:23]=1[C:24]([CH3:26])=[CH:25][C:8]([CH3:28])([CH3:7])[NH:9]2
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1ccccc13
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1=CC(C)(C)Nc2ccc(-c3ccccc3O)c(CO)c21
Reaction time: 1 h

Procedure:
Under argon atmosphere, lithium aluminum hydride (1.48 g, 39.0 mmol) was suspended in anhydrous tetrahydrofuran (30 mL). A solution of 2,2,4-Trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-1, 3.80 g, 13.0 mmol) in anhydrous tetrahydrofuran (40 mL) was added dropwise at 0° C. and the reaction mixture was stirred at the same temperature for 1 hour. Ethyl acetate (15 mL) and water (5 mL) were added dropwise successively to the reaction mixture and then 0.2 N aqueous HCl solution (350 mL) was added thereto. The whole was extracted with ethyl acetate (300 mL, 100 mL). The combined organic layer was washed with water (300 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the titled reference compound (4.01 g) as a pale brown solid. (Yield quantitative)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][C:21]#[N:22]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[C:20](=[CH:7]/[C:6]2[S:5][C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:3][C:2]=2[CH3:1])/[C:21]#[N:22])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: Cc1nc(-c2ccccc2)sc1C=O
Product: COc1ccc(/C(C#N)=C/c2sc(-c3ccccc3)nc2C)cc1OC
Yield: 92.1 %

Procedure:
4-Methyl-2-phenyl-1,3-thiazole-5-carbaldehyde (407 mg) was condensed with 3,4-dimethoxybenzyl cyanide (354 mg) through Method A (production step 2), to thereby yield the target product (yield: 667 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20](O)([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20]([CH2:24][CH2:25][CH3:26])=[CH:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCCC(O)(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC=C(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 110 °C
Yield: 81.4 %

Procedure:
4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol (594 mg) and p-toluenesulfonic acid monohydrate (74 mg) were combined in 13 mL toluene and the stirred mixture was heated to 110° C. for 11 h. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was washed with additional ethyl acetate. The combined ethyl acetate was washed with brine, dried with magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 461 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, which was recrystallized from hexane, mp 86.7-88.2° C.
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([C:30]1[C:38]([O:39][CH3:40])=[CH:37][C:36]([CH3:41])=[C:35]2[C:31]=1[CH:32]=[CH:33][N:34]2C(OC(C)(C)C)=O)([C:11]1[N:15](COCC[Si](C)(C)C)[C:14]2[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:13]=2[N:12]=1)[CH3:10])=O)(C)(C)C.C(OC(N(C)C(C1C(OC)=CC(C)=C2C=1C=CN2C(OC(C)(C)C)=O)(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)C)=O)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[CH3:40][O:39][C:38]1[C:30]([C:9]([C:11]2[NH:15][C:14]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:13]=3[N:12]=2)([NH:8][CH3:6])[CH3:10])=[C:31]2[C:35](=[C:36]([CH3:41])[CH:37]=1)[NH:34][CH:33]=[CH:32]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Product: CNC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 0 °C

Procedure:
A mixture of (±)-tert-butyl 4-(1-((tert-butoxycarbonyl)(methyl)amino)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-((tert-butoxycarbonyl)(methyl)amino)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.21 g, 0.304 mmol) was dissolved in anhydrous MeOH (0.61 mL) and cooled to 0° C. A 4 M HCl solution in dioxane (1.52 mL, 6.09 mmol) was added and the reaction was stirred in the ice bath for 5 hours. Anhydrous MeOH (0.6 mL) was added to the reaction followed by cesium carbonate (2.98 g, 9.13 mmol). The mixture was heated at 60° C. for 1 hour. At this point the reaction was concentrated and diluted with a saturated solution of aq. ammonium chloride and ethyl acetate. The layers were separated and the organic phase was dried over magnesium sulfate, concentrated and purified by flash chromatography [0-5% MeOH (containing 10% ammonium hydroxide) in DCM] to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (br. s., 1H) 7.93 (m) 7.56 (m) 7.43-7.50 (m, 1H) 7.22 (br. s., 1H) 6.69 (s, 1H) 6.57 (br. s., 1H) 3.22 (s, 3H) 2.44 (s, 3H) 2.06 (s, 3H) 1.91 (s, 3H). HRMS calcd. for C21H21N5O (M+H) 360.1824. found 360.1831.
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]2[CH2:10][C@H:11]3[C@H:16]([CH2:17][C:8]=2[CH:7]=[CH:6][C:5]=1[O:18]C)[NH:15][CH2:14][CH2:13][CH2:12]3.[BrH:20]>>[BrH:20].[NH:15]1[C@@H:16]2[C@H:11]([CH2:10][C:9]3[C:4]([OH:3])=[C:5]([OH:18])[CH:6]=[CH:7][C:8]=3[CH2:17]2)[CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc2c(c1OC)C[C@@H]1CCCN[C@H]1C2
Agent: Br
Agent: Cl
Product: Oc1ccc2c(c1O)C[C@@H]1CCCN[C@H]1C2
Temperature: 170 °C
Reaction time: 1 h

Procedure:
Intermediate III (16 mg) was placed in a microwave reactor vial and 48% HBr (1 mL) was added. The reactor was sealed, and the mixture was stirred at 170° C. for 1 h under microwave irradiation. The precipitated product was filtered off and dried in vacuo. Yield of example 2a2: 11 mg as a solid. LC/MS (method 17): RT 1.27 min, ELSD 88%, UV 75.1%, MH+: 220.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][NH:8][C:9]2[C:18]([CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C([O-])(=O)C.[K+].C(O)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][NH:8][C:9]2[C:18]([CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[Cl:34])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2CCC(=O)NCC2CCCCC2)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2nc3ccc(-c4ccccc4Cl)cc3cc2CCC(=O)NCC2CCCCC2)cc1
Temperature: 85 °C

Procedure:
To a stirred solution of (E)-3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)acrylamide (3.7 g, 7.3 mmol, prepared as in Example 2) in DME (100 mL) was added 4-methylbenzenesulfonohydrazide (13.6 g, 72.8 mmol). The mixture was brought to reflux at 86° C. and then via addition funnel was added dropwise a solution of sodium acetate (10.4 g, 127 mmol) in water (60 mL) over 1.5 h. Once the addition was complete, the reaction was refluxed for an additional 30 min, and then cooled to RT and concentrated to remove organic solvent. The crude material was dissolved in DCM (150 mL) and washed sequentially with 1N NaOH, 1N HCl, and then water. The organic layer was dried over MgSO4, filtered and concentrated to give a yellow oil, which upon purification via flash chromatography (5% EtOAc/DCM) afforded 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)propanamide. Step 2 In a sealed tube was combined 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)propanamide (0.16 g, 0.31 mmol), 2-chlorophenylboronic acid (0.074 g, 0.47 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.0044 g, 0.0063 mmol), potassium acetate (0.062 g, 0.63 mmol), ethanol (6.0 ml) and water (0.41 mL). The flask was sealed and heated in an oil bath at 85° C. for 16 h. The reaction mixture was cooled to RT, adsorbed onto silica and purified by flash chromatography (5% MeOH/DCM) to afford 3-(2-(4-methoxybenzylamino)-6-(2-chlorophenyl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide. Step 3 The product of step 2 was carried through the same procedure as described in Step 9, Example 2, to afford 3-(2-amino-6-(2-chlorophenyl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide. MS (ESI, pos. ion) m/z: 422 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:37][CH3:38])=[C:7](/[CH:20]=[CH:21]/[C:22]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])[CH:8]=[C:9]([C:11]2[C:12]([O:18]C)=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br.C([O-])(O)=O.[Na+]>CC(O)=O>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[C:29]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:30]=[CH:31][C:22]=1/[CH:21]=[CH:20]/[C:7]1[CH:8]=[C:9]([C:11]2[C:12](=[O:18])[NH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]=1[O:37][CH3:38]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(C)nc2OC)cc(C(C)(C)C)c1OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(C)[nH]c2=O)cc(C(C)(C)C)c1OC
Yield: 58.9 %

Procedure:
step 1—A solution of 308 (89 mg, 0.165 mmol), HBr 48% (0.090 mL, 0.784 mmol) in HOAc (4 mL) was heated at 50 overnight in a sealed tube. The reaction mixture was carefully poured into a mixture of saturated NaHCO3 and ice, extracted with EtOAc, and dried (Na2SO4). The crude product was purified on a preparative SiO2 TLC plate developed with 2:1 EtOAc/hexane to afford 51 mg of a white solid that was further purified by HPLC to afford 33 mg of I-201 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)#[N:10]>C(O)(C)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[CH:14][C:13]2[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: Nc1ccc(F)cc1
Solvent: CC(C)O
Product: N#Cc1cccc(C=Nc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
88 ml of para-fluoroaniline are added dropwise to 12 g of meta-cyanobenzaldehyde in 60 ml of isopropanol. After 1 h at 60° C., the product precipitates out. The mixture is allowed to warm to room temperature and filtered off, and the residue is washed with isopropanol. Drying gives 11 of m.p. 101° C.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[Cl:6][C:7]([Cl:13])([Cl:12])[C:8](=[NH:11])OC>C1(C)C=CC=CC=1>[Cl:6][C:7]([Cl:13])([Cl:12])[C:8]([NH:5][NH:4][C:1](=[O:3])[CH3:2])=[NH:11]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CC(=O)NN
Solvent: Cc1ccccc1
Product: CC(=O)NNC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5.0 g (0.07 mole) acetylhydrazine and 20 ml (28.5 g, 0.16 mole) methyl 2,2,2-trichloroacetimidate was stirred 16 hours at room temperature. The resulting solid was recrystallized from toluene to yield 7.3 g. Addition of petroleum ether to the filtrate gave another 1.5 g. The total yield was 8.8 g (59%; mp 130°-132° C.). An analytical sample (mp 131°-132° C.) was prepared by recrystallization from toluene. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[O:20]1CCOC[CH2:21]1.C[O-].[Na+]>CO>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCO1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1

Procedure:
1.96 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine was dissolved in 35 ml. of a mixture of dioxan and methanol (1:1), 0.84 g. sodium methylate added thereto, the reaction mixture heated under reflux for 1 hour, the solution then evaporated in a vacuum, the residue triturated with water, filtered with suction and dried at 120° C. in a vacuum. There was thus obtained 0.64 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-methoxy-s-triazolo[4,3-b]pyridazine, which has a melting point of 193° - 198° C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[CH3:41])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)CC(c1cccc(CN(C)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (203 mg), formaldehyde solution (88 μL) and acetic acid (67 μL) in acetonitrile (3.9 mL) was added sodium triacetoxyborohydride (125 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated sodium hydrogen carbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (148 mg) as a colorless transparent oil.