Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[N:21]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:30]2)[N:21]=1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)ccc3C#N)C2)nc1N
Temperature: 120 °C

Procedure:
55 mg (0.19 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 60.9 mg (0.23 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 11A) and 0.169 ml (0.97 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 30 mg (33% of theory) of the product were obtained in solid form.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8]/[C:9](/[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[N:10]\[C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>ClCCl>[CH3:44][S:41]([NH:1][C:2]1[N:7]=[C:6]([NH:8]/[C:9](/[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:32])[F:33])=[N:10]\[C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(N/C(=N\C(=O)c2ccc(C(F)(F)F)cc2)NCc2ccccc2C(F)(F)F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(N/C(=N\C(=O)c2ccc(C(F)(F)F)cc2)NCc2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
(Z)-N-(((6-Aminopyridin-2-yl)amino)((2-(trifluoromethyl)benzyl)amino) methylene)-4-(trifluoromethyl)benzamide (200 mg, 0.42 mmol) was dissolved in dichloromethane (3.8 mL) and pyridine (0.4 mL) was added followed by mesyl chloride (32 μL, 0.42 mmol). The reaction was stirred at room temperature for 3 days, and another equivalent of mesyl chloride (32 μL, 0.42 mmol) was added, and stirring continued for another 24 h. The crude material then was concentrated, and the residue was partitioned between water and ethyl acetate, and the organic layer was washed with brine, then dried over sodium sulfate, and concentrated in vacuo to provide the crude product. The crude product was purified by chromatography (gradient: 8:2 hexanes:EtOAc to 2:8 hexanes:EtOAc) to provide the title compound (95 mg, 41% yield).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([CH2:29][CH2:30][CH3:31])[CH:4]=1)#[N:2].[SH2:32].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([CH2:29][CH2:30][CH3:31])[CH:4]=1)=[S:32]
Reactant: S
Reactant: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of ethyl {(1S)-5-[3-(4-cyano-2-propylphenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (Example 143, 1.2 g, 2.9 mmol) in DMF (anhydrous, 15 mL) under argon at rt was passed H2S gas at a moderate rate for 20 min. Then, a solution of diethylamine (0.3 g, 4.3 mmol) in DMF (3 mL) was added in one portion, and the reaction mixture was stirred at 60° C. for 3 h. Upon completion, the reaction was cooled to rt and argon was passed through the reaction mixture for 1 h to remove residual H2S. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:1) to give 0.9 g (76%) of the title compound as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 0.94 (t, 3H), 1.31 (t, 3H), 1.52-1.64 (m, 2H), 1.65-1.80 (m, 1H), 2.20-2.44 (m, 4H), 2.58-2.95 (m, 5H), 3.38-3.61 (m, 1H), 4.16-4.21 (m, 4H), 4.26 (t, 2H), 6.69 (d, 1H), 6.80 (s, 1H), 6.95 (d, 1H), 7.09 (d, 1H), 7.79 (d, 1H), 7.84 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (1 g, 5.8 mmol) in 20 mL of anhydrous DMF was added 2-(4-methyl-1-piperazinyl)ethanol (1.09 g, 7.6 mmol). Sodium hydride (60%) (467 mg, 11.68 mmol) was added portionwise. The reaction was stirred at rt for 30 min at which time the reaction was diluted with ethyl acetate and washed with water and a saturated sodium chloride solution. Solvents were removed under reduced pressure to give 1.7 g of crude 1-methyl-4-(2-{[3-(methyloxy)-4-nitrophenyl]oxy}ethyl)piperazine as a yellow solid. ESIMS (M+H)+=296.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29]>CN(C)C=O>[C:12]([O:11][C:1](=[O:10])[CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)o2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of di-tert-butyl malonate (4.3 g, 19.91 mmol, 1.99 equiv) and potassium carbonate (2.8 g, 20.29 mmol, 2.03 equiv) in N,N-dimethylformamide (30 mL) was stirred at 65° C. for 30 min A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.65 g, 10.00 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was then added dropwise with stiffing to the reaction mixture. The resulting solution was stirred at 65° C. overnight and then quenched with 60 mL of ice and water. The mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers was washed with 3×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 4.0 g (90%) of methyl 4-(4-(3-tert-butoxy-2-(tert-butoxycarbonyl)-3-oxopropyl)-5-methyloxazol-2-yl)benzoate as a light yellow solid. LC-MS: (ES, m/z): 446 [M+H]+, 390, 334, 272, 230, 115.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH:16]([N:19]=[C:20]=[O:21])([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:17][CH:16]([NH:19][C:20]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:21])[CH3:18]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 39.4 %

Procedure:
To a stirred and chilled (10°-20° C.) solution of 9.0 g (0.042 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of dry methylene chloride was added dropwise 4.1 g (0.048 mole) of isopropyl isocyanate. The reaction mixture was stirred at room temperature for 2 hr and was diluted with 100 ml of methylene chloride. The solution was washed with 5% sodium hydroxide (2×40 ml), water (50 ml), saturated sodium chloride (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was crystallized from ethyl acetate, affording 7.6 g (60.6%). Recrystallization from ethyl acetate gave 5.0 g of clear white needles, m.p. 150°-151.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:2].[CH2:45]1[O:53][C:52]2[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][C:47]=2[O:46]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:25]=[C:26]([C:50]3[CH:49]=[CH:48][C:47]4[O:46][CH2:45][O:53][C:52]=4[CH:51]=3)[CH:27]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCc3ccccc3)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Yield: 93.8 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-benzyloxy-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (260 mg, 0.39 mmol), 3,4-methylenedioxyphenylboronic acid (127 mg, 0.78 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (253 mg, 0.78 mmol) to obtain 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-benzyloxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (260 mg, 94%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C43H50O9 (M+Na)+ 733.3347. found 733.3345.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[C:32]([Sn](CCCC)(CCCC)CCCC)=[CH:31][N:30]=[CH:29]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cn1cncc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 89.8 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.0 g, 2.46 mmol), 1-methyl-5-(tributylstannyl)imidazole (prepared according to Gaare, K., et al. Acta Chem. Scand. (1993), 47(1), 57-62) (1.25 g, 3.37 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic amount) were reacted according to Procedure B in dioxane (50 ml) for 3 hours. The solvent was removed in vacuo, and the solid was washed with i-hexane. The resulting dark solid was suspended in IMS, and undissolved material removed by filtration. The resulting filtrate was concentrated in vacuo to give the product as a pale baige solid (0.90 g, 2.21 mmol, 90%);_δH [2H6]-DMSO 9.69 (1H, b, NH), 8.60 (1H, s, 5-H), 8.55 (1H, s, 2-H), 8.00 (1H, d, 7-H), 7.83 (2H, m, 8-H, imidazole-H), 7.69 (2H, d, 2′-H, 6′-H), 7.52-7.33 (5H, m, 5×Ph-H), 7.22 (1H, s, imidazole-H), 7.09 (2H, d, 3′-H, 5′-H), 5.14 (2H, s, CH2), 3.80 (3H, s, CH3); m/z 408 (M+1)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH3:16].[CH:17](N1CCCCC1)=[O:18].Cl>O1CCCC1.BrC(Br)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:17]=[O:18])[C:10]=1[CH3:16]
Reactant: O=CN1CCCCC1
Reactant: Cc1c(Br)cccc1COC1CCCCO1
Agent: CC(Br)Br
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(C=O)cccc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
1.2 g of Mg (magnesium turnings) in 15 ml of absolute tetrahydrofuran are initially taken under a nitrogen atmosphere. A few drops of dibromoethane are added at 65° C. A solution of 14.25 g of 3-bromo-2-methylbenzyl tetrahydro-2-pyranyl ether in 50 ml of tetrahydrofuran is added dropwise while the temperature is kept at 65° C. The stirred mixture is then refluxed for 2 hours. A solution of 5.65 g of N-formylpiperidine in 10 ml of absolute tetrahydrofuran is added dropwise to the reaction mixture, which has been cooled to 0° C. Stirring is carried out for 20 hours at room temperature and the mixture is rendered slightly acidic with about 50 ml of 5% strength hydrochloric acid and is extracted several times with ether. The combined ether extracts are washed with water, dried and evaporated down. The crude product (11 g) can be purified by column chromatography over silica gel using 97.5:2.5 toluene/acetone.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]([CH2:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([OH:20])[CH3:21])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cccc(Cl)c3n2CC(C)(O)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
6-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.5 mmol) was dissolved in 15 mL DMF and stirred for 5 min at RT. Sodium hydride (540 mg, 13.5 mmol) was added portionwise at RT under nitrogen. 3-(2-Methyl-oxiranyl)-pyridine (800 mg, 5.9 mmol) was diluted in 5 mL DMF and added dropwise at the same temperature and stirred for 16 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water (30 mL) and filtered. The residue was crystallized in EtOH (1 mL) and ether (40 mL) and purified by reverse phase chromatography to obtain 620 mg of 1-(6-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.77 (s, 1H), 8.5 (d, 1H), 8.45 (s, 1H), 7.71 b (s, 1H), 7.17 b (s, 1H), 7.06 (d, 1H), 6.97 (t, 1H), 5.12 b (s, 1H), 4.3 b (s, 1H), 3.78 (m, 1H), 3.62 (m, 1H), 3.14 (m, 1H), 2.63 (m, 2H), 2.57 (s, 3H), 2.5 b (s, 2H), 1.53 (s, 3H). Separation by chiral HPLC provided enantiomers 57a and 57b.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[N:28]=[C:27]([NH:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]4)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:16]=[CH:17][CH:18]=1)=[O:11])=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[N:28]=[C:27]([NH:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]4)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:16]=[CH:17][CH:18]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)[C@H]5CCCN5C(=O)C(F)(F)F)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)[C@H]5CCCN5)c4)nc4ccccc34)ccc21
Temperature: 25 °C

Procedure:
To a suspension of tert-butyl 5-(2-(3-((R)-1-(2,2,2-trifluoroacetyl)-pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.15 mmol) in MeOH (5.7 mL) and H2O (345 mL) was added K2CO3 (108 mg, 0.78 mmol). Reaction mixture was refluxed for 2 h. Cooled to RT temperature and concentrated in vacuo. The residue was dissolved in EtOAc and extracted with H2O (3×). Dried the organic layer under Na2SO4 and concentrated in vacuo. The aqueous layer was basicified with 1 N NaOH, extracted with CHCl3 (3×), dried under Na2SO4 and concentrated in vacuo. The two organic layers were combined to afford tert-butyl 5-(2-(3-((R)-pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (65 mg, 79%).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:4]=1[CH:16]1[CH2:18][CH2:17]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O.CCOC(C)=O>[CH:16]1([C:4]2[C:5](=[O:15])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]([CH3:8])[C:3]=2[CH2:2][O:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(CBr)c(C2CC2)c(=O)n1-c1ccccc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cn1c(COc2ccc(F)cc2)c(C2CC2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of 5-bromomethyl-4-cyclopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.094 g) in acetonitrile (5 mL), was added 4-fluorophenol (0.034 g), caesium carbonate (0.1 g) and potassium iodide (3 crystals). The reaction was stirred overnight at ambient temperature and was then diluted with water and EtOAc. The phases were separated and the aqueous was extracted with further EtOAc. The combined organic phases were washed with further HCl solution, brine and dried with sodium sulfate. Filtration and evaporation of the volatiles in vacuo afforded the desired 4-cyclopropyl-5-(4-fluoro-phenoxymethyl)-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.023 g) as a light beige solid. MS (ESI+): 339.1 ([M+H]+).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22](O)=[O:23].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:14]3[O:13][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH:15]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccccc2o1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzofuran-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.29-7.38 (m, 1H), 7.44-7.52 (m, 1H), 7.57 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H). MS (DCI/NH3) m/z 297. Anal. Calculated for C18H20N2O2.HCl: C, 64.96; H, 6.36; N, 8.42. Found: C, 64.51; H, 6.23; N, 8.14.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].O[C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C@@H:16]1[CH2:17][CH2:12][CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: CCOc1ccccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccccc1O[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of 2-ethoxyphenol (13.72 g, 99 mmol), tert-butyl (S)-3-hydroxypiperidine-1-carboxylate (20 g, 99 mmol), and triphenylphosphine (29 g, 111 mmol) in toluene (150 mL) at 20-25° C. was added a solution of DIAD (20 mL, 104 mmol) in toluene (50 mL) over 2 hours. After 2 hours, the reaction mixture was filtered and washed with diethyl ether (300 mL). The filtrate was washed with 3N NaOH (150 mL), dried over Na2SO4, and concentrated. The crude residue was purified via column chromatography to afford tert-butyl (R)-3-(2-ethoxyphenoxy)piperidine-1-carboxylate (14.6 g, 45%). MS (ES+) 222.2 (M-100+H).
Reaction SMILES: ClCCl.CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:26][C@H:25]2[CH2:27][OH:28])=[CH:17][N:16]=1>O.C(N(CC)CC)C>[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:26][C@H:25]2[CH:27]=[O:28])=[CH:17][N:16]=1
Reactant: Cc1nc(Cl)ncc1OC[C@@]1(c2cccc(F)c2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(Cl)ncc1OC[C@@]1(c2cccc(F)c2)C[C@H]1C=O
Temperature: -78 °C
Yield: 126.4 %

Procedure:
A dichloromethane (25 ml) solution of dimethyl sulfoxide (5 ml) was added dropwise to a dichloromethane (100 ml) solution of oxalyl chloride (2.98 ml), while the solution was stirred at −78° C. The obtained mixture was stirred at −78° C. for 10 minutes, and a dichloromethane (25 ml) solution of the compound 323-1 (5.67 g) was then added dropwise to the reaction mixture. The obtained mixture was stirred at −78° C. for 30 minutes. Thereafter, triethylamine (14.7 ml) was added to the reaction mixture, and the obtained mixture was stirred for 2 hours, while it was heated to 0° C. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, so as to obtain the title compound (7.12 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([N:9]=[C:10]([O:12][CH2:13]C)[CH3:11])=C[O-])=[O:5])[CH3:2].[K+].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:9]=[C:10]([CH3:11])[O:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=C[O-])N=C(C)OCC
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(C)n1
Temperature: 110 °C
Yield: 44.9 %

Procedure:
5 g (25 mmol) of potassium 2-ethoxycarbonyl-2-(1-ethoxy-ethylideneamino)-ethenolate were completely dissolved in 15 mL acetic acid at RT, and then the solution was heated to 110° C. overnight. After cooling down, 100 mL EtOAc were added and the solution is neutralized with saturated NaHCO3 solution. The organic phase was separated, dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 1:2) yielded 1.74 g (45%) of 2-methyl-oxazole-4-carboxylic acid ethyl ester as an yellow oil, MS: 156 (MH+).