Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:6][C:7](=[O:9])[CH3:8])(=[O:3])[CH3:2].BrC[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl-].[CH2:28]([Al+]CC)C>C1COCC1.[Zn]>[C:1]([O:4][CH:5]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:6][C:7]([OH:9])([CH3:28])[CH2:8][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(C)=O
Reactant: CCOC(=O)CBr
Reactant: CC[Al+]CC
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)CC(C=Cc1ccc(Cl)cc1Cl)OC(C)=O
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A solution of 6-(2,4-dichlorophenyl)-2-oxo-5-hexene-4-yl acetate (1.3 g, 4.3 mmole) and ethyl bromoacetate (0.47 ml, 4.2 mmole) in dry THF (10 ml) was added dropwise to a vigorously stirred slurry of activated zinc dust (490 mg, 7.5 mmole), cuprous bromide (29 mg, 0.2 mmole), diethylaluminum chloride (25% solution in toluene; 1.72 ml, 4.3 mmole) and dry THF (5 ml) under N2 at 20° C. Stirring was continued for 5 hours before quenching with pyridine (3.5 ml). After the addition of water (50 ml) the mixture was extracted with ether (3×80 ml). The combined ether extracts were washed with 1 N HCl (2×25 ml), H2O (2×50 ml) and brine, then dried (MgSO4), filtered and evaporated leaving the crude title compound as a pale yellow oil (1.2 g); pmr (CDCl3) δ1.28 (3 H, t), 1.33 (3H, t), 2.10 (3H, s).
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][N:22]([CH3:24])[CH3:23])[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].S(OCCCCCCCCC=CCCCCCCCC)(=O)(=O)C.CN(C)CC(O)CO.[OH:76][CH2:77][CH2:78][C:79](=[O:94])[CH2:80][CH2:81][C:82](=[O:93])[CH2:83][CH2:84][O:85][C:86](=[O:92])[CH2:87][CH2:88][CH2:89][CH2:90][Br:91]>CC(C)=O>[Br-:91].[CH2:1]([O:19][CH:20]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][N+:22]([CH2:90][CH2:89][CH2:88][CH2:87][C:86]([O:85][CH2:84][CH2:83][C:82](=[O:93])[CH2:81][CH2:80][C:79](=[O:94])[CH2:78][CH2:77][OH:76])=[O:92])([CH3:24])[CH3:23])[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]
Reactant: O=C(CCO)CCC(=O)CCOC(=O)CCCCBr
Reactant: CCCCCCCCC=CCCCCCCCCOCC(CN(C)C)OCCCCCCCCC=CCCCCCCCC
Agent: CCCCCCCCC=CCCCCCCCCOS(C)(=O)=O
Agent: CN(C)CC(O)CO
Solvent: CC(C)=O
Product: CCCCCCCCC=CCCCCCCCCOCC(C[N+](C)(C)CCCCC(=O)OCCC(=O)CCC(=O)CCO)OCCCCCCCCC=CCCCCCCCC
Product: [Br-]
Yield: 24 %

Procedure:
A mixture of (2,3-bis-octadec-9-enyloxypropyl)-dimethylamine 4 (378 mg, 0.61 mmol) (synthesised from octadec-9-enyl mesylate and 3-dimethylamino-1,2-propanediol as described previously by Hurley et al., J. Org. Chem., 2004, 69, 980-984) and 3 (335 mg, 1.07 mmol) in acetone (5 ml) was stirred in a sealed-tube at 80° C. for 48 h. After cooling, the solvent was evaporated in vacuo. Purification by flash chromatography on silica (gradient; 5% to 10% methanol in dichloromethane) gave ME42 as an orange oil (140 mg, 27%).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([N:18]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:46][O:47][C:48]1[CH:75]=[CH:74][C:51]([CH2:52][N:53]([CH2:61][C:62]2[CH:63]=[C:64]3[C:69](=[CH:70][CH:71]=2)[CH2:68][C@@H:67](CN)[CH2:66][CH2:65]3)[CH2:54][CH:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[CH:50][CH:49]=1>CN(C=O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:18]([C@H:67]3[CH2:66][CH2:65][C:64]4[C:69](=[CH:70][CH:71]=[C:62]([CH2:61][N:53]([CH2:52][C:51]5[CH:50]=[CH:49][C:48]([O:47][CH3:46])=[CH:75][CH:74]=5)[CH2:54][CH:55]5[CH2:60][CH2:59][O:58][CH2:57][CH2:56]5)[CH:63]=4)[CH2:68]3)[CH3:16])=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: COc1ccc(CN(Cc2ccc3c(c2)CC[C@H](CN)C3)CC2CCOCC2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc3c(c2)CC[C@H](N(C)C(=O)c2ccc(C4CCCCC4)cc2)C3)CC2CCOCC2)cc1

Procedure:
A mixture of 4-cyclohexylbenzoic acid (45 mg), DMF (1 ml), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (hydrochloride, 45 mg) and 1-hydroxybenzotriazole (32 mg) was admixed after 5 minutes with diisopropylethylamine (30 mg) and ((S)-6-{[(4-methoxybenzyl)-(tetrahydropyran-4-ylmethyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl)methylamine (80 mg). Volatile fractions were removed after 12 hours. The residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 594.84 (C28H38N2O3); MS (ESI) 595 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=O.[F:17][C:18]([F:25])([F:24])[C:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:10][NH:23][CH2:22][C:19]1([C:18]([F:25])([F:24])[F:17])[CH2:21][CH2:20]1
Reactant: C[Si](C)(C)OC(C=O)c1c(Cl)cccc1Cl
Reactant: NCC1(C(F)(F)F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)OC(CNCC1(C(F)(F)F)CC1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of crude 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde (0.35 g, 1.263 mmol) in DCM (6.31 ml) was added (1-(trifluoromethyl)cyclopropyl)methanamine (0.176 g, 1.263 mmol) and NaBH(OAc)3 (0.374 ml, 2.53 mmol) and stirred for 2 h at ambient temperature. The reaction was quenched with aqueous sat NH4Cl solution and diluted with DCM (50 mL). Organic layer was passed through phase separator and concentrated to obtain 2-(2,6-dichlorophenyl)-N-((1-(trifluoromethyl)cyclopropyl)methyl)-2-((trimethylsilyl)oxy)ethanamine (0.378 g, 70%) as light yellow oil. This was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[N:33]=[C:32]([CH3:34])[C:31]([OH:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:35][C:31]4[C:32]([CH3:34])=[N:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cc1nc(S(C)(=O)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(S(C)(=O)=O)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 160 °C
Yield: 40.9 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 6-methanesulfonyl-2-methyl-pyridin-3-ol (Intermediate 6; 36 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted with dichloromethane and the solvent was evaporated to give 4-[4-(6-methanesulfonyl-2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 42%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.50 (s, 9H), 1.96-2.06 (m, 2H), 2.20-2.34 (m, 2H), 2.92-3.05 (m, 2H), 4.26-4.39 (m, 2H), 4.92-5.04 (m, 1H), 7.76 (d, 1H, J=8.4 Hz), 8.06 (d, 1H, J=8.4 Hz), 8.21 (s, 1H), 8.46 (s, 1H). Mass spectrum (ES) MH+=489. HRMS Calcd. for C22H29N6O5S (MH+): 489.1915. Found: 489.1915.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].C1(C)C=CC=CC=1>O>[CH:1]([C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc2ccccc2s1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C(=Cc1nc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 2-methylbenzothiazole (1.49 g, 0.01 mol), benzaldehyde (1.27 g, 0.012 mol), 50% sodium hydroxide solution (3 ml), toluene (5 ml) and compound 1 (1 mmol) was stirred at reflux temperature for 4 hours. The reaction mixture was allowed to cool to room temperature and then diluted with water (10 ml). The organic layer was separated and the aqueous phase extracted with toluene. The combined organic portions were dried over magnesium sulphate and evaporated to give a solid residue which was crystallized from ethanol to give the corresponding 2-styrylbenzothiazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][S:29][CH:28]([C:32](O)=[O:33])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][S:29][CH:28]([C:32]([N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:33])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C1CN(C(=O)OC(C)(C)C)CCS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (150 mg), thiomorpholine-2,4-dicarboxylic acid 4-tert-butyl ester (137 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg), and dimethyl aminopyridine (92 mg) in dichloromethane (15 ml) was stirred at room temperature overnight. After the addition of water (10 ml), the mixture was extracted with 10 ml ethyl acetate three times. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography on silica (20-33% ethyl acetate in hexane) to give the desired product as a resin: MS (m+1)=499.4.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[CH:14]1[C:19]([CH:20]=O)=[CH:18][C:17]2[O:22][CH2:23][O:24][C:16]=2[CH:15]=1.[OH-].[Na+]>C(O)C>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:2](=[O:3])[CH:1]=[CH:20][C:19]1[CH:14]=[CH:15][C:16]2[O:24][CH2:23][O:22][C:17]=2[CH:18]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a warm (40° C.) solution of 41.5 grams (0.23 mole) of 3,4-dimethoxyacetophenone and 40.5 grams (0.27 mole) of piperonal in 220 milliliters of ethanol was added 60 milliliters of 10 % aqueous sodium hydroxide. The mixture was warmed for 10 minutes at 40°-50° C; then stirred at room temperature for 2 hours. After standing overnight, the yellow crystalline produce was collected by filtration, washed with water (3 × 40 milliliters), and dried to give 72 grams (quantitative yield) of V, melting point 127°-129° c. An analytical sample was prepared by recrystallization of 1.6 gram of the product from 50 milliliters of ethanol, giving 1.4 gram of pure chalcone as yellow needles, melting point 131°-133° C.; λ (ethanol) 242 (log ε 4.23), 3.60 nm (4.53).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([N:20]3[CH2:23][CH:22]([OH:24])[CH2:21]3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[NH:25]1CCCC[CH2:26]1.O1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([OH:40])([C:38]#[CH:39])[CH3:37]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:39]#[C:38][C@@:36]([OH:40])([C:32]4[N:25]=[CH:26][CH:35]=[CH:34][N:33]=4)[CH3:37])[CH:15]=3)[C:10]([C:18]([N:20]3[CH2:23][CH:22]([OH:24])[CH2:21]3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2nc(C(=O)N3CC(O)C3)c3ccc(I)cc32)n1
Reactant: C1CCNCC1
Reactant: C#CC(C)(O)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@@](O)(C#Cc1ccc2c(C(=O)N3CC(O)C3)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
To a pressure tube was added 1-{[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]carbonyl}azetidin-3-ol (150 mg, 0.34 mmol) followed by piperidine (2.0 mL), Pd(PPh3)4 (39.74 mg, 0.03 mmol), copper(I) iodide (6.5 mg, 0.03 mmol) and 2-(1,3-oxazol-2-yl)but-3-yn-2-ol (70.74 mg, 0.5 mmol). The reaction vessel was capped and stirred at 35° C. for 2.5 hr. The reaction mixture was concentrated in vacuo. DCM (5 mL×2) added and the mixture was concentration in vacuo. The crude material purified by column chromatography (elution with 1-10% MeOH in DCM) and was then triturated from a MeCN/Ether mixture (3:1) to give the title compound: 1H NMR (DMSO-d6, 500 MHz) delta 1.94 (3H, s), 3.87 (1H, dd, J=10.4, 3.9 Hz), 4.31-4.44 (2H, m), 4.51-4.64 (1H, m), 4.88 (1H, dd, J=9.9, 6.9 Hz), 5.83 (1H, d, J=6.5 Hz), 6.81 (1H, s), 7.12 (1H, d, J=5.5 Hz), 7.18 (2H, s), 7.24 (1H, s), 7.46 (1H, d, J=8.4 Hz), 8.16 (1H, s), 8.27 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=5.5 Hz), 8.96 (1H, s). LC-MS: m/z+388.05 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:8][S:7][CH:6]=1)=[O:4].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:12]([CH3:13])[C:11]([NH:10][C:9]2[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=2)=[O:15])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cscc1NC(=O)C(C)Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(Oc1ccc(C(C)(C)C)cc1)C(=O)Nc1cscc1C(=O)O

Procedure:
In analogy to Example 2, the title compound was prepared using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester and 4-tert-butylphenol. MS (m/e): 346.2 (M−H).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[K+].C(O)(=O)C>CO.O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[C:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]2=[O:11])=[CH:22][CH:23]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCCc2ccccc21
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C=C2CCc3ccccc3C2=O)cc1

Procedure:
A mixture of 3,4-dihydro-1(2H)-naphthalenone (4.5 g) and 4-tertbutylbenzaldehyde (5.0 g) was stirred with a solution of 4% potassium hydroxide in methanol (100 ml) for 64 hours at room temperature. The mixture was neutralised with glacial acetic acid, followed by dilution with water (100 ml). The resulting copious white precipitate was filtered off, washed with water and dried in vacuo to give 2-(4-tertbutylbenzylidene)-3,4-dihydro-1(2H)-naphthalenone.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[N:14]=[C:13]2[C:25]1[N:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]2)[CH:28]=[N:27][CH:26]=1.[F:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O>>[F:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][CH:49]=[CH:48][C:47]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[N:14]=[C:13]2[C:25]1[N:30]=[C:29]([N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[CH2:35][CH2:36]2)[CH:28]=[N:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Reactant: COc1cccc(B(O)O)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cccc(-c2ccc3c(c2)c(-c2cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)n2)nn3C2CCCCO2)c1F
Temperature: 150 °C
Yield: 54 %

Procedure:
To a 5 mL conical microwave vial was added potassium phosphate (Aldrich, 129 mg, 0.61 mmol), PdCl2AmPhos (17.1 mg, 0.02 mmol), tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e, 135 mg, 0.24 mmol), and 2-fluoro-3-methoxyphenylboronic acid (Frontier Scientific, 45.3 mg, 0.27 mmol) which was sealed, evacuated and back-filled with N2 3×. Dioxane (2.0 mL) and water (0.4 mL) were added and the resulting mixture was heated at 150° C. for 30 min with microwave irradiation. After the reaction mixtures were filtered, the crude reaction mixture was concentrated under reduced pressure. The dark brown residue was dissolved with DMSO, filtered, and purified by HPLC (5% 0.1% TFA in water to 95% 0.1% TFA in ACN over 20 min) to give tert-butyl 1-(6-(5-(2-fluoro-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (78.1 mg, 53.5%). MS (ESI, pos. ion) m/z: 603 (M+1). A mixture of 5N HCl in IPA (25.9 μL, 0.13 mmol), tert-butyl 1-(6-(5-(2-fluoro-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (78.1 mg, 0.13 mmol), DCM (1.3 mL) and MeOH (1.3 mL) was heated at 80° C. for 30 min with stirring. The resulting reaction mixture was cooled to RT and concentrated to a yellow solid. The above solid was stirred with a 1:1 mixture of DCM:MeOH and applied to a pre-washed (10 mL MeOH) column of Si-propylsulfonic acid (Silicycle, Cat# R51230B). The compound was released with 30 mL of MeOH (with 2M NH3) to yield the title compound product as a yellow oil. MS (ESI, pos. ion) m/z: 419 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.NCCCCCCN[C:18]1[C:19]2[C:24]([N:25]=[C:26]3[C:31]=1[CH:30]=[CH:29][CH:28]=[CH:27]3)=[CH:23][CH:22]=[CH:21][CH:20]=2.CO>C(Cl)(Cl)Cl>[CH:20]1[C:19]2[C:24](=[N:25][C:26]3[C:31]([CH:18]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][CH:21]=1
Reactant: NCCCCCCNc1c2ccccc2nc2ccccc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccc2nc3ccccc3cc2c1
Reaction time: 1 h

Procedure:
To a solution of 76 mg (0.168 mmol) of TFP ester 4 in 3 mL of chloroform was added 94 μL of triethylamine (0.67 mmol). 1.23 ml of a 50 mg/mL solution of 9-(6-aminohexylamino)acridine dihydrochloride in methanol (61.5 mg, 0.168 mmol) was added to the stirred solution. HPLC analysis after 1 hour showed complete reaction of the starting TFP ester. The reaction mixture was partitioned between 15 mL of methylene chloride and 10 mL of water. The organic phase was washed with 10 mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel and the desired product was eluted with a gradient of 90:5:5-methylene chloride: triethylamine:methanol in hexanes. Removal of solvents gave the desired product 5 as a red solid: TLC (90:5:5-methylene chloride: triethylamine:methanol) Rf =0.79; 1H NMR (CDCl3) δ 8.12 (d, 2H, J=8.8 Hz,), 8.07 (d, 2H, J=8.8 Hz), 7.68 (t, 2H, J=6.9 Hz), 7.37 (t, 2H, J=7.4 Hz), 5.60 (s, 1H), 5.2 (br s, 1H), 3.82 (t, 2H, J=7.1 Hz), 3.21 (q, 2H, J=6.6 Hz), 2.54 (m, 2H), 2.2 (m, 10H), 1.98 (s, 3 H), 1.8-1.65 (m, 6H), 1.5-1.3 (m, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)CCCCCCCCCCC.[CH3:18][O:19][C:20](=[O:34])[CH2:21][C:22]1[C:26]2[CH:27]=[CH:28][C:29]([O:32]C)=[C:30]([CH3:31])[C:25]=2[S:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:34])[CH2:21][C:22]1[C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[C:30]([CH3:31])[C:25]=2[S:24][CH:23]=1
Reactant: COC(=O)Cc1csc2c(C)c(OC)ccc12
Agent: CCCCCCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1csc2c(C)c(O)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a mixture of aluminum chloride (3.30 g) and toluene (30 mL) was added 1-dodecanethiol (17.80 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. To the mixture was added methyl(6-methoxy-7-methyl-1-benzothiophen-3-yl)acetate (3.1 g) at room temperature. The mixture was stirred at room temperature for 13 h. The mixture was quenched with ice water at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.580 g).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].N1C=CC=CC=1.[C:22]12([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>C(Cl)Cl.CCOC(C)=O>[C:22]12([CH2:32][C:33]([NH:1][N:2]3[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:15])=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: CC(C)c1nn(N)c(=O)c2ccccc12
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1nn(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(=O)c2ccccc12
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of the product of Example 1B (45.4 mg, 0.223 mmol), pyridine (0.023 mL, 0.28 mmol), and (adamantan-1-yl)acetyl chloride (0.052 g, 0.24 mmol) in CH2Cl2 (0.8 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (eluted with 8% EtOAc/CH2Cl2) to give the title compound (0.0743 g, 0.196 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.35 (dd, 1H), 8.10 (d, 1H), 7.98 (td, 1H), 7.89 (ddd, 1H), 3.62 (quin, 1H), 2.03 (s, 2H), 1.95 (s, 3H), 1.76-1.52 (m, 12H), 1.26 (d, 6H); MS (ESI−) M/Z 378.1 (M−H)−.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]([CH2:11][C@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C(C)(C)C)=[O:25])=[C:20]([F:31])[CH:19]=2)[CH2:13]1)=[N+:9]=[N-:10]>C(Cl)Cl>[N:8]([CH2:11][C@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[C:20]([F:31])[CH:19]=2)[CH2:13]1)=[N+:9]=[N-:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
60% TFA in DCM (5 mL) was added to 5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one (0.336 g, 1 mmol), and the solution kept at r.t. for 1 h. Solvents were removed in vacuo to afford 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (0.280 g, 99%). A mixture of 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one well stirred mixture of (0.080 g, 0.286 mmol) and thiosemicarbazide (0.0957 g, 0.286 mmol) in dioxane (2 mL) was heated until the mixture was homogeneous. Phosphorous oxychloride (0.027 ml, 0.29 mmol) was added, and the mixture heated at reflux for 1 h. The mixture was allowed to cool to r.t., and the white precipitate filtered, washed with dioxane, suspended in saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. Combined oganic extracts were washed with brine, and dried (MgSO4) Solvent was removed under vacuum, and the crude product purified by PTLC (10% MeOH in DCM) to give product as a white solid (0.038 g, 40%); MS (m/z): [M+H]+=336.