Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[H-].[Na+].CI.[C:47](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][CH3:47])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in N,N-dimethylformamide (1 ml), then thereto is added sodium hydride (63%,11 mg) under ice-cooling, and the mixture is stirred at 0° C. for 30 minutes. Methyl iodide (23 μl) is added thereto, and the mixture is stirred for 2 hours under ice-cooling. To the reaction mixture is added 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-methoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (120 mg). MS (m/z): 614 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([N:24]([CH2:40][CH3:41])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=O)[C:33]2=[CH:32][CH:31]=1)=[O:29])[CH3:23].Cl>C1COCC1.O1CCOCC1>[CH2:40]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:33]2=[CH:32][CH:31]=1)=[O:29])[CH3:41]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1ccc2c(n1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (76 mg, 0.46 mmol) in THF (3 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1M solution in THF, 1.2 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (2-diethylamino-ethyl)-amide (70 mg, 0.25 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and is poured into a cold 4M HCl solution in dioxane (3 mL) at 0° C. The resulting mixture is stirred at room temperature overnight. The reaction mixture is concentrated to partially remove the dioxane and is then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase is collected and the aqueous phase is extracted with additional EtOAc. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The residue is purified by chromatography (silica gel, MeOH-Chloroform). The product containing fraction are concentrated and the residue is treated with EtOAc-hexane (1:1). The solid is collected by filtration to give the title compound as an orange solid (51 mg, 49%).
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH2:7][C:6]1=O)(OC)=[O:2].C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].[O-]CC.[Na+]>CCO>[N:16]1[C:6]2[CH2:7][S:8][CH2:9][C:5]=2[C:1](=[O:2])[NH:17][CH:15]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1CSC2
Temperature: 90 °C

Procedure:
Commercially available 4-carbomethoxytetrahydro-3-thiophenone (5 g, 31.2 mmol) is dissolved in EtOH (284 mL). Formamidine acetate (22 g, 211 mmol) is then added followed by sodium ethoxide (45 mL, 121 mmol, 21% w/w) and the mixture is heated at 90° C. for 14 hours. Reaction is cooled to room temperature and concentrated to a residue which is absorbed onto silica and separated via FCC (0-10% Methanol:CH2Cl2) to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][O:16][CH3:17])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1([CH3:57])[O:49][C@H:48]([CH2:50][N:51]2[CH:55]=[CH:54][C:53]([NH2:56])=[N:52]2)[CH2:47][O:46]1>ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][O:16][CH3:17])[C:11]([NH:56][C:53]2[CH:54]=[CH:55][N:51]([CH2:50][C@@H:48]3[CH2:47][O:46][C:45]([CH3:57])([CH3:44])[O:49]3)[N:52]=2)=[O:13])[C:7](=[O:18])[CH:6]=1
Reactant: COCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.1 %

Procedure:
In a round bottom flask under argon was placed (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methoxy-butyric acid (62 mg, 0.19 mmol) in dichloromethane (5 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (37 μL, 0.21 mmol) and 1-hydoxybenzotriazole (27 mg, 0.20 mmol) and stirred at 25° C. for 2 h. After this time period, 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 45 mg, 0.23 mmol) was added and stirred for 16 h at 25° C. After this time, the reaction was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (4 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-4-methoxy-butyramide (26 mg, 27%) as a colorless oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[C:13]([F:15])[C:12]([NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=23)=[C:11]([F:27])[CH:10]=1)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[Pd]>[F:27][C:11]1[CH:10]=[C:9]([NH2:8])[CH:14]=[C:13]([F:15])[C:12]=1[NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=12
Reactant: [H][H]
Reactant: Cc1c[nH]c2nccc(Nc3c(F)cc(N(Cc4ccccc4)Cc4ccccc4)cc3F)c12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1c[nH]c2nccc(Nc3c(F)cc(N)cc3F)c12

Procedure:
66 mg of 10% palladium-on-carbon are added to a solution of 280 mg (0.62 mmol) of N4,N4-dibenzyl-2,6-difluoro-N1-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine in 20 ml of ethanol and 1.85 ml (1.85 mmol) of 1 M hydrochloric acid, and the suspension is stirred in a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through Celite, the Celite is washed with methanol and the filtrate is then concentrated under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1.[NH2:19][C@@H:20]([CH2:23][CH3:24])[CH2:21][OH:22]>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:19][CH:20]([CH2:21][OH:22])[CH2:23][CH3:24])[N:11]=2)=[CH:6][CH:5]=1
Reactant: CC[C@H](N)CO
Reactant: COC(=O)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(CO)Nc1ncc(Cl)c(-c2ccc(C(=O)OC)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(2,5-Dichloropyrimidin-4-yl)-benzoic acid methyl ester (70 mg, 0.25 mmol) was dissolved in ethanol with 0.22 g, 2.5 mmol, of (S)-2-aminobutan-1-ol and the reaction mixture was heated to 80° C. for 6 hours, then allowed to stand at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 0.5 N HCl, brine, dried over sodium sulfate and concentrated to an oil, which was purified by chromatography on silica (EtOAc 20 to 60% in hexanes) to afford 4-[5-chloro-2-(1-hydroxymethylpropylamino)-pyrimidin-4-yl]-benzoic acid methyl ester as a colorless oil, 68 mg, 0.20 mmol, 80%. 1H NMR 500 MHz (CDCl3): 8.24 (s, 1H), 8.10 (d, 2H), 7.78 (d, 2H), 5.23 (m, 1H), 3.96 (m, 1H), 3.94 (s, 3H), 3.78 (m, 1H), 3.63 (m, 1H), 2.84 (br s, 1H), 1.56 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH3:29][C:30]1[C:31]([CH:36]=O)=[N:32][CH:33]=[CH:34][CH:35]=1.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:36][C:31]2[C:30]([CH3:29])=[CH:35][CH:34]=[CH:33][N:32]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: Cc1cccnc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: Cc1cccnc1CNCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 3-methylpyridine-2-carboxaldehyde (24.2 mg) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (59.3 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1O.CC1CCCC(C(C)(C)C)C1=O.[NH3:25].C1(=O)CCCCC1>[Pd].O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[NH2:25]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: N
Agent: [Pd]
Agent: CC1CCCC(C(C)(C)C)C1=O
Solvent: O=C1CCCCC1
Solvent: O
Product: Cc1cccc(C(C)(C)C)c1N

Procedure:
In a pressure reaction vessel was placed 0.55 mole parts of 2-methyl-6-tert-butylphenol, 0.55 mole parts of 2-methyl-6-tert-butylcyclohexanone, 0.0045 mole parts of palladium (5 weight per cent on charcoal support) and 3 mole parts of ammonia. The vessel was sealed and, while stirring, heated to 250°C. (Water was not added in this example because the initial reaction of ammonia with cyclohexanone produced 0.55 mole part of water.) The mixture was stirred at this temperature for 3 hours and then cooled and distilled, giving a 46.8 per cent conversion to 2-methyl-6-tert-butyl aniline. The yield of 2-methyl-6-tert-butyl aniline based on consumed phenol was about 98 per cent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:25][C:26]([CH:28]=[CH2:29])=[O:27].C(O)(=O)/C=C\C(O)=O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:29][CH2:28][C:26](=[O:27])[CH3:25])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(OCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: C=CC(C)=O
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC(=O)CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.7 g (2.1 mM) of 1-[2-(bis-(4-fluorophenyl) -methoxy)-ethyl]piperazine and 150 mg (2.1 mM) of freshly distilled methylvinyl-ketone was stirred at room temperature for 2 h. 30 ml of ethanol and 0.48 g of maleic acid were added, the precipitated salt was isolated by filtration and recrystallized from hot acetonitrile to yield the dimaleate salt of the title compound as colourless crystals melting at 159°-160° C. Analytical data were in accordance with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:46][C@@H:47]([C:59]1[S:60][C:61]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[C:62]([C:64]([NH2:66])=[O:65])[N:63]=1)[CH2:48][C:49]1[CH:58]=[CH:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=1>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:46][C@@H:47]([C:59]1[S:60][C:61]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[C:62]([C:64](=[O:65])[NH2:66])[N:63]=1)[CH2:48][C:49]1[CH:58]=[CH:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=1)[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NC(=O)c1nc([C@H](N)Cc2ccc3ccccc3c2)sc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(N)=O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 115.5 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (0.107 g; 0.341 mmol) was dissolved in methylene chloride/dimethyl formamide (5:1; 20 ml). 1-Hydroxybenzotriazole (0.046 g; 0.341 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.071 g; 0.369 mmol) were added. The reaction mixture was stirred 15 min at room temperature and 2-((1R)-1-amino-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide (0.106 g; 0.284 mmol) was added. The reaction mixture was stirred 12 hours at room temperature. The reaction mixture was washed with water (20 ml), sodium hydrogensulfate (10%; 20 ml), sodium hydrogencarbonate (satd; 20 ml), water (20 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×15 cm) using ethyl acetate/heptane (2:1) as eluent to afford 0.22 g of ((1R)-1-((1R)-1-(4-carbamoyl-5-phenyl-1,3-thiazole-2-yl)-2-(2-naphthyl)-ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([O:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:18]1[CH:19]=[C:20]([S:24][CH2:25][CH2:26]OS(C)(=O)=O)[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([O:32][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH2:25][CH2:26][N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[CH:19]=2)[C:9]2[S:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:34][CH2:35]1
Reactant: c1c[nH]nn1
Reactant: CN1CCC(OC(c2cccc(SCCOS(C)(=O)=O)c2)c2nc3ccccc3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(SCCn3nccn3)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,3-triazole (36.5 mg) in N,N-dimethylformamide (1 mL) is added a dispersion of sodium hydride 60% in mineral oil (1 molar equivalent). The reaction mixture is stirred at room temperature for 15 minutes, then a solution of methanesulfonic acid 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl ester (85 mg) in N,N-dimethylformamide (1 mL) is added. The reaction mixture is stirred at 60° C. overnight. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane/methanol/ammonia 100/0/0 to 90/10/1) to afford 2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7](OCC)(=[O:10])[C:8]#[CH:9].C1(C)C=CC=CC=1>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1
Reactant: Nc1cc[nH]n1
Reactant: C#CC(=O)OCC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Oc1ccn2nccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-aminopyrazole (11.5 g, 0.138 mol) in 65 mL of 1,4-dioxane was added ethyl propiolate (14.7 g, 15.2 mL, 0.150 mol) dropwise, and the resultant light yellow solution was warmed to reflux. After 4 h, the blood-red solution was cooled to room temperature and 100 mL of toluene was added with stirring. The resultant precipitate was collected with toluene and air-dried to afford the title compound as a tan solid. MS 136.0 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])=[O:4].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]([NH:5][NH:6][CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: COC(=O)NN=C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)NNC(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.6 %

Procedure:
N′-Isopropylidene-hydrazine-carboxylic acid methyl ester (6.45 g) were dissolved in ethanol (50 mL) and acetic acid (50 mL) PtO2 (0.231 g) was added, and reaction was stirred at room temperature for 22 hours under an atmosphere of hydrogen. Mixture was evaporated under vacuum, giving N′-Isopropyl-hydrazine-carboxylic acid methyl ester (5.08 g, 77%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:26])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH3:25])[C:17](=[O:24])[N:18]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]3=[CH:12][CH:11]=2)[CH:9]=1)(=O)[CH3:2].[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CO.[Ti](Cl)(Cl)(Cl)Cl>[CH3:22][C:20]([CH3:23])([CH3:21])[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C:8]3[CH:9]=[C:4]([C@H:1]([N:27]4[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]4)[CH3:2])[CH:5]=[CH:6][C:7]=3[CH3:26])=[CH:11][CH:12]=2)[N:16]([CH3:25])[C:17]1=[O:24]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc([C@@H](C)N2CCS(=O)(=O)CC2)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a microwave vial was added 5-(5-acetyl-2-methylphenyl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (15-7) (30 mg, 0.085 mmol) and thiomorpholine 1,1-dioxide (17 mg, 0.13 mmol) were added under nitrogen and dissolved in toluene (0.43 ml). Titanium(IV) chloride (10 mg, 0.05 mmol) was added to the solution and the reaction was allow to stir at room temperature overnight. Sodium cyanoborohydride (8 mg, 0.12 mmol) was then added and allowed to stir for 1 hour. The reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 1-(2,2-dimethylpropyl)-5-{5-[(1R)-1-(1,1-dioxidothiomorpholin-4-yl)ethyl]-2-methylphenyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (36-1). HRMS (M+H)+: observed=471.2421, calculated=471.2424.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[CH2:38][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3([CH2:30][O:29][C:28]4[CH:31]=[C:32]5[C:36](=[CH:37][C:27]3=4)[CH2:35][CH2:34][O:33]5)[C:18]2=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Cc1cccc(N)c1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1cccc(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using m-toluidine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (81%) as a colorless solid: mp 229-231° C.; 1H NMR (300 MHz, CDCl3) δ8.85 (s, 1H), 7.64-7.55 (m, 2H), 7.49-7.42 (m, 1H), 7.40-7.33 (m, 2H), 7.32-7.16 (m, 4H), 7.11-7.03 (m, 2H), 6.96 (d, J=7.6 Hz, 1H), 6.40 (s, 2H), 5.22-5.05 (m, 2H), 4.93 (d, J=9.0 Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.52 (t, J=8.7 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 2.35 (s, 3H); MS (ES+) m/z 525.11 (M+23).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17]CCC)=O)=[CH:10][CH:9]=[C:8]([O:21]C)[N:7]=1)=O.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:17][O:16][C:14]1[N:5]=[C:6]2[C:11]([CH2:10][CH2:9][C:8](=[O:21])[NH:7]2)=[CH:12][CH:13]=1
Reactant: CCCCOC(=O)CCc1ccc(OC)nc1NC(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c(n1)NC(=O)CC2
Temperature: 80 °C
Yield: 78.6 %

Procedure:
A mixture of butyl 3-[2-[(2,2-dimethylpropanoyl)amino]-6-(methyloxy)-3-pyridinyl]propanoate (86.01 g, 256 mmol) in hydrochloric acid (500 ml, 3000 mmol) (6M aqueous), was heated at 80° C. for 6 h. Reaction was cooled, treated with water (500 ml), transferred to a 5 L conical flask and carefully neutralised with solid potassium carbonate (requires around 250 g) (much effervescence was observed). The mixture was then extracted with 20% MeOH/DCM (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude product as a yellow solid (35.84 g, 79%).