Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Li]CCCC.[CH3:17][C:18]1([CH3:21])[CH2:20][O:19]1.CO>C1COCC1>[CH3:17][C:18]([OH:19])([CH3:21])[CH2:20][C:8]1[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:11]=[CH:10][N:9]=1
Reactant: c1cn(C2CCCCO2)cn1
Reactant: CC1(C)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)Cc1nccn1C1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To the solution of 1-(tetrahydro-pyran-2-yl)-1H-imidazole (7.6 g, 50 mmol) in dry THF (500 ml) at −78° C. was added n-BuLi solution (2.5 M in hexanes, 25 mL, 60 mmol, 1.2 equiv). The reaction mixture was slowly warmed to 0° C. and stirred at 0° C. for 30 min. After it was cooled to −78° C., 2,2-dimethyloxirane (7.2 g, 100 mmol) was added and it was stirred for 1 h. The reaction mixture was warmed to r.t. slowly and stirred at r.t. overnight. MeOH was added and the reaction mixture was concentrated by a rotary evaporator. Water (30 ml) was added and it was extracted with CH2Cl2 (15 ml×3). The organic layer was dried over MgSO4, concentrated, and purified by neutral Al2O3 column chromatography (CH2Cl2: MeOH=100:1) to give 8 gm of 2-methyl-1-[1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-propan-2-ol (75%). 1H NMR (CDCl3): δ 7.04 (s, 1H), 6.95 (s, 1H), 5.13 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.82 (d, J=12.0 Hz, 2H), 2.01-1.89 (m, 4H), 1.92 (m, 1H), 1.69-1.60 (m, 3H), 1.24 (m, 6H)
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:20])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:20]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(C(C)C)cc2C1=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.83 h
Yield: 95 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 50 minutes while stirring through a solution, cooled to -70°, of 5.6 g of (RS)-2-(2-buten-1-yl)-6-isopropyl-1-indanone in 125 ml of anhydrous dichloromethane and 25 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.7 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 60 ml of dichoromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 50 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 5.08 g (95%) of (RS)-2-(2-oxoethyl)-6-isopropyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1)=[O:18]>>[CH2:27]([O:26][C:22]1[CH:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:34]=[CH:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][C:15]=2[NH:14][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)Nc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2C(=O)Nc2cccc(OCc3ccccc3)c2)cc1
Yield: 41.2 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (3.5 mmol) and 2-amino-N-(3-benzyloxyphenyl)-4-nitrobenzamide (3.2 mmol) yielded 0.69 g (69%) of the title product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[I-].[Na+].C([O-])([O-])=O.[K+].[K+].Cl.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:31]1[CH:30]=[C:29]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[CH2:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=4[CH:16]=3)[CH2:37][CH2:36]2)[C:28]([Cl:27])=[C:33]([Cl:34])[CH:32]=1
Reactant: O=C1CCc2ccc(OCCCCCl)cc2N1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Temperature: 25 °C
Yield: 159.6 %

Procedure:
A mixture of 100 gm 7-(4-chloro butoxy)-3,4-Dihydrocarbostyril in 600 ml acetonitrile with sodium iodide (88.6 gm), K2CO3 (109 gm), Tetrabutylammonium bromide (TBAB) (0.5 gm) and 1-(2,3-dichlorophenyl)piperazine hydrochloride (110 gm) was stirred at ambient temperature. The reaction mixture was refluxed and maintained at reflux until reaction completes. The reaction mass was cooled at room temperature. DM Water (500 ml) was added to reaction mass and stirred for 30 min at ambient temperature. The mass was filtered and washed with water till pH of filtrate came to 7.0-7.5. The solid was dried in hot air oven at 60° C. to give Aripiprazole.
Reaction SMILES: [CH2:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6](O)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].CS(Cl)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C(Cl)Cl.CCN(CC)CC>[N:29]([CH:6]([Si:5]([CH2:1][CH2:2][CH:3]=[CH2:4])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:9])[CH3:10])=[N+:30]=[N-:31]
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C(O)CC(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C(CC(C)C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 34 (1.68 g, 5.16 mmol) in CH2Cl2 (100 mL) and Et3N (3.6 mL) at 0° C. was added dropwise over 5 min methanesulfonyl chloride (2.96 g, 25.8 mmol), and the solution was allowed to warm to rt over 1 h. After stirring overnight under argon, the mixture was cooled to 0° C. and quenched with water (50 mL). The organic layer was isolated and the aqueous layer extracted twice with 20-mL portions of CH2Cl2. The combined organic extracts were concentrated in vacuo at rt. The crude mesylate was dissolved in DMF (100 mL), and to this solution was added sodium azide (1.68 g, 25.8 mmol). After stirring for 8 h at rt, the mixture was partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was isolated and aqueous layer extracted twice with 50-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 35 as a colorless oil (1.57 g, 87%): R.function. =0.90 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ7.57 (d, J=6.7 Hz, 4H), 7.41 (m, 6H), 5.88 (m, 1H), 5.00 (dd, J=17.0, 1.5 Hz, 1H), 4.92 (dd, J=10.2, 1.5 Hz, 1H), 3.44 (d, J=12.4 Hz, IH), 10 2.12 (m, 2H), 1.84 (m, 1H), 1.60 (t, J=12.5 Hz, 1H), 1.30 (m, 3H), 0.92 (d, J=6.7 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ140.7, 135.3, 132.6, 129.9, 128.0, 113.3, 49.2, 38.8, 27.5, 25.9, 23.3, 20.7, 10.5; IR (neat) 3071 (w), 3051 (w), 2995 (w), 2957 (s), 2923 (m), 2866 (m), 2102 (s), 1642(w), 1473 (w), 1432(s), 1264(m), 1188(w), 1116(s), 1004(w), 915 (m), 743 (s), 701 (s) cm-1 ; MS (FAB) m/e (rel. intensity) 350 (MH+, 18), 323 (32), 322 (100), 321 (27), 320 (16), 315 (42), 306 (42), 252 (17), 251 (23), 237 (18), 236 (73), 223 (26), 208 (17); HRMS (FAB) calcd for C21H28N3Si: 350.2053, found: 350.2040. Anal. Calcd for C21H27N3Si: C, 72.16; H, 7.79; N, 12.02. Found: C, 71.99; H, 7.91; N, 11.60.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][S:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:3]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CSc2nc(Cl)cc(Nc3cc(C)n[nH]3)n2)cc1
Reactant: CN1CCNCC1
Product: COc1ccc(CSc2nc(Nc3cc(C)n[nH]3)cc(N3CCN(C)CC3)n2)cc1

Procedure:
The above-prepared [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.38 mmol) in 1-methylpiperazine (10 mL) is heated at 130° C. for 15 hours. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO2, dichloromethane/MeOH gradient) to give the desired product [2-(4-methoxy-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH2:11]([CH:10]1[O:30][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][CH3:21])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCC1OC1CCCCCCCC(=O)OC

Procedure:
Methyl oleate (1) (5.0 g; 0.017 mol) (89%) (ITERG) and meta-chloroperbenzoic acid (mCPBA) (4.3 g; 0.025 mol) (Aldrich) were dissolved in dichloromethane (J. T. Baker) (100 mL) and the reaction mixture was mixed under agitation at ambient temperature for 5 hours. The reaction mixture was then filtered and the collected solution was washed with saturated aqueous sodium bicarbonate (3×50 mL) (Aldrich) then with water (3×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. Finally, the solvent was removed by evaporation under rotation to obtain the intermediate compound 2.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:56][CH2:57][CH2:58][C:59]([CH3:69])([O:61][Si:62]([CH2:67][CH3:68])([CH2:65][CH3:66])[CH2:63][CH3:64])[CH3:60]>O1CCCC1.C(OCC)(=O)C.O>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:56][CH2:57][CH2:58][C:59]([O:61][Si:62]([CH2:67][CH3:68])([CH2:63][CH3:64])[CH2:65][CH3:66])([CH3:60])[CH3:69])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)OC(C)(C)CCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 100 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (200 mg, 0.367 mmol), sodium hydride (60% in oil, 45 mg, 1.125 mmol) and 15-crown-5 (80 mg, 0.363 mmol) in tetrahydrofuran (1 ml), was added 1-bromo-4-methyl-4-(triethylsilyloxy)pentane (220 mg, 0.745 mmol) at room temperature, followed by reflux under heating for 1 hour. The reaction solution was diluted with ethyl acetate, followed by the dropwise addition of water under cooling with ice and washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the thus obtained residue was purified by column chromatography (hexane:ethyl acetate=15:1) to give the titled compound (278.7 mg, quant.) as a colorless oil.
Reaction SMILES: [CH2:1]([C:9](Cl)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[S:12]1[CH:16]=[C:15]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[N:14]=[CH:13]1>N1C=CC=CC=1>[CH2:1]([C:9]([N:21]1[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=[C:17]1[C:15]1[N:14]=[CH:13][S:12][CH:16]=1)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: CCCCCCCCC(=S)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=S)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
249 G. (1.19 moles) of n-octylthiocarbonyl chloride is added dropwise over a period of 20 minutes to a stirred suspension of 240 g. (1.19 moles) of 2-(4-thiazolyl)-benzimidazole and 2400 ml. of pyridine; a slight heat rise is evidenced. The reaction mixture is stirred at room temperature for 19 hours, filtered and the solid material washed with methylene chloride. The combined filtrate and washings are evaporated to dryness in vacuo. The residue is mixed with 2000 ml. of methylene chloride and filtered. The solid material is washed with methylene chloride and the combined filtrate and washing are wased twice with water, 3 times with cold 0.25 normal hydrochloric acid (5000 ml. total volume), once with saturated cold sodium bicarbonate and twice with water. The methylene chloride is dried, evaporated to dryness in vacuo affording a syrupy oil which crystallizes under vacuum. The solid material is dissolved in 3 liters of hexane and filtered and the hexane evaporated to a small volume and diluted with petroleum ether to a volume of 3000 ml. whereupon crystallization results. The solid material is filtered and washed with cold petroleum ether affording 219.8 g. (54%) of pure 1-n-octylthiocarbonyl-2-(4-thiazolyl)-benzimidazole, melting point 58° to 59° C.
Reaction SMILES: C[N:2]1[CH2:11][C:10]2([CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1>[CH2:24]([O:23][C:21]([N:2]1[CH2:11][C:10]2([CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CN1Cc2ccccc2C2(Cc3ccccc3O2)C1
Solvent: c1ccccc1
Product: CCOC(=O)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Yield: 74.7 %

Procedure:
A solution of 2'-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (26.1 g) and ethyl chloroformate (12.4 g) is heated under reflux in benzene (275 ml) overnight. The reaction mixture is washed with water (3x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield 24 g (76%) of product as a solid, mp 65°-75°. A sample is thrice recrystallized from hexane to yield the product, mp 89°-90°.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1>[C:17]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: OC[C@H]1CC[C@H](O)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of trans-4-(hydroxymethyl)cyclohexanol (1.8 g, 14 mmol, Tetrahedron Lett. 1970, 11, 4281-4284.), triethylamine (2.4 mL, 17 mmol), and N,N-dimethylaminopyridine (0.34 g, 3.0 mmol) in tetrahydrofuran (70 mL) was added acetic anhydride (1.4 mL, 15 mmol) at room temperature. After being stirred at room temperature for 48 h, the mixture was concentrated in vacuo to give an oil. The residual oil was extracted with ethyl acetate (100 mL). The organic layer was washed with successively 2N hydrochloric acid, aq. sodium hydrogencarbonate, and brine. The extract was dried over magnesium sulfate and concentrated in vacuo give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 1:1 to 1:2) to give 1.2 g (50%) the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Reaction time: 4 h

Procedure:
A solution of (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (1.0 g, 6.60 mmol) in ethanol (30 mL) was added to a suspension of 10% palladium-on-carbon (500 mg) in ethanol at room temperature. The reaction mixture was hydrogenated for 4 h using a balloon filled with hydrogen gas. The mixture was filtered through a pad of Celite and the filtrate was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:5][C:4]([C:13]([F:16])([F:15])[F:14])=[N:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:12][C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:5]=2)=[CH:8][N:9]=1)=[O:21]
Reactant: Cn1nc(C(F)(F)F)cc1-c1cnc(N)s1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)cc1-c1cnc(NC(=O)c2c(F)cccc2F)s1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a mixture of 5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole-2-ylamine (63, 4.6 mg, 0.019 mmol) in 0.5 ml DCM were added 2,6-difluorobenzoyl chloride (5 μl, 2 eq), DIEA (17 μl, 3 eq) and DMAP (2 mg). After stirred at r.t for overnight, the reaction mixture was worked up with DCM/aq. NaCO3, the DCM phase was concentrated to dryness. The solid residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1). 0.1 ml of 1N NaOH were added and mixture was stirred at r.t for 1 h before worked up DCM//aq. NaCO3. DCM phase was concentrated and subjected to silica gel flash column to give 5.6 mg of (2,6-difluorophenyl)-N-{5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl] (1,3-thiazol-2-yl)}carboxamide (64) as white solid (yield: 75.9%; purity>95%). LC-MS: calcd. for C15H9F5N4OS: 389 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]([CH3:28])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[CH3:28]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Agent: Cl
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine hydrochloride (CAN 1240526-27-5) as starting materials, and isolated (64 mg, 84%) as light yellow solid; LC-MS (UV peak area, ESI) 100%, 358.1869 (M+H).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].OP([O-])([O-])=O.[Na+].[Na+].Br[CH2:39][CH2:40][O:41]C1CCCCO1.[I-].[K+]>CN(C=O)C.C(N(CC)CC)C>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:39][CH2:40][OH:41])[CH2:26][CH2:25]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CCO)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 30.4 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (100 mg, 0.23 mmol) in DMF (2 mL) was added sodium phosphate dibasic (107 mg, 0.75 mmol), triethylamine (2 drops) and 2-(2-bromo-ethoxy)-tetrahydro-pyran (38 μL, 0.25 mmol). The resultant mixture was stirred overnight at RT before a further addition of triethylamine (100 μL) was made. The reaction was stirred at 50° C. for 5 hours then allowed to stand at RT over the weekend. The reaction was heated to 50° C. and stirred overnight before the addition of 2-(2-bromo-ethoxy)-tetrahydro-pyran (38 μL, 0.25 mmol) and potassium iodide (10 mg, 0.06 mmol) then stirred overnight at 55° C. The solution was cooled and loaded onto a SCX-2 cartridge, washed with MeOH then eluted with 2M NH3 in MeOH. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) this gave 288 (31 mg, 0.07 mmol, 31%). LCMS: RT=2.59 min, [M+H]+ 437. 1H NMR δ (ppm) (CDCl3): 8.42 (1H, d, J=8.30 Hz), 7.58 (1H, s), 7.00 (1H, dd, J=8.34, 1.83 Hz), 6.88 (1H, d, J=1.78 Hz), 5.93-5.83 (1H, m), 4.46-4.43 (2H, m), 4.41-4.37 (2H, m), 3.70 (2H, t, J=5.19 Hz), 3.17 (2H, d, J=11.24 Hz), 2.68 (2H, t, J=5.17 Hz), 2.62-2.50 (1H, m), 2.38 (3H, s), 2.36-2.27 (2H, m), 2.05-1.85 (4H, m), 1.54 (6H, d, J=6.65 Hz). OH not observed
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6](Br)[CH:5]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1.COC(=O)C1C=C(NC2C=NC=CC=2)C=C(C2C=CC=C3C=2C=CN3)C=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)c1cc(Br)cc(Br)c1
Agent: COC(=O)c1cc(Nc2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Product: COC(=O)c1cc(Br)cc(Nc2cccnc2)c1

Procedure:
3-Bromo-5-(pyridin-3-ylamino)-benzoic acid methyl ester was prepared from 3,5-dibromo-benzoic acid methyl ester and pyridin-3-ylamine in low yield as described for Example 36, except that the reaction was run at 130° C. This material was converted to 3-(1H-indol-4-yl)-5-(pyridin-3-ylamino)-benzoic acid methyl ester by the method of Example 35. 1H NMR (400 MHz, CDCl3): δ 8.43 (d, J=14.4 Hz, 2H), 8.20 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.29-7.24 (m, 2H), 7.22-7.16 (m, 2H), 6.69 (s, 1H), 5.93 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][CH:13]([CH3:36])[CH:14]([NH:19][C:20]([C:22]1[S:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)=[CH:25][N:26]=1)=[O:21])[C:15]([O:17][CH3:18])=[O:16]>>[CH:1]1([CH2:7][CH2:8][C:9]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([C:24]3[S:23][C:22]([C:20]([NH:19][CH:14]([CH:13]([CH3:36])[CH3:12])[C:15]([O:17][CH3:18])=[O:16])=[O:21])=[N:26][CH:25]=3)=[CH:28][CH:29]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C(Cl)CCC1CCCCC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)CCC3CCCCC3)cc2)s1)C(C)C
Yield: 49 %

Procedure:
The title compound was synthesized analogous to Example 27, using 3-cyclohexylpropanoyl chloride and intermediate 2. Yield: 49%; 1H NMR (DMSO-d6, 300 MHz): δ 10.09 (s, 1H), 8.74 (d, 1H), 8.35 (s, 1H), 7.71 (s, 4H), 4.32 (t, 1H), 3.69 (s, 3H), 2.36 (t, 2H), 2.30 (m, 1H), 1.73 (m, 5H), 1.51 (q, 2H), 1.17 (m, 4H), 0.96 (t, 6H), 0.92 (m, 2H); MS (ESI) m/z 472.0 [M+H]+.