Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2]1>CO.[Pd]>[O:1]1[CH2:2][CH:3]([N:5]2[CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CCC(C2CCN(C3COC3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: C1CC(C2CCN(C3COC3)CC2)CCN1
Yield: 114.4 %

Procedure:
520 mg (1.45 mmol) of benzyl 1′-(oxetan-3-yl)-[4,4′-bipiperidine]-1-carboxylate was dissolved in 30 ml methanol and hydrogenated in the H-cube® flow hydrogenator using a 10 mol % Pd (C) cartridge at a flow rate of 1 ml/min. The solvent was removed in vacuo providing 372 mg of the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1.O>CN(C)C=O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g; that is prepared as described in Reference Example 36) in dry dimethylformamide (270 mL) under nitrogen is treated portionwise with potassium carbonate (79.5 g). After stirring at room temperature for 45 minutes, it is treated with cyclopentyl bromide (34.3 mL), and the resulting suspension is heated at 60° C. for 8 hours. After cooling, the solution is evaporated to low bulk under reduced pressure, to give an oil. This oil is treated with water (250 mL) and diethyl ether (300 mL), and the aqueous layer is washed with further quantities of diethyl ether (2×50 mL). The combined ethereal extracts are washed with brine (1×50 mL) and with water (3×50 mL), dried over magnesium sulfate and evaporated. The resulting residue is crystallized from methanol, to give 4-benzyloxy-3-cyclopentyloxybenzaldehyde (79 g), m.p. 55°-56° C. [Elemental analysis: C,77.1; H,6.9%; calculated: C,77.0; H,6.8%].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C@:20]2([CH3:26])[CH2:24][O:23]C(=O)[NH:21]2)[CH:14]=[CH:13]3)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)C.[OH-].[Li+].O>>[NH2:21][C@@:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][C:8]3[CH:27]=[CH:28][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH:11]=2)[CH:16]=1)([CH3:26])[CH2:24][OH:23]
Reactant: CC(C)Oc1ccc(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(R)-4-[6-(4-isopropoxy-phenoxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (1.092 g, 0.002894 mol) was dissolved in ethanol (60 mL, 1 mol), followed by 4 M lithium hydroxide in water (30 mL, 0.1 mol). The reaction mixture was then heated at 80° C. for 5 hours. LCMS indicates no SM remains with mostly DP RT=1.26 min, M+1=352. All solvent was removed under reduced pressure. The solid was triturated with DCM, and the solvent was then washed with water. Organic was dried over MgSO4, filtered and concentrated to dryness. Residue was then placed on the high vac for 5 hours. 1H NMR and LCMS were consistent with structure. ESI-MS: 360 (M−16)+ 1H NMR (400 MHz, CHLOROFORM-d) δ=7.88-7.67 (m, 3H), 7.50-7.21 (m, 5H), 7.00 (m, 2H), 6.45-6.13 (m, 1H), 4.82-4.67 (m, 1H), 4.43 (s, 2H), 2.17 (s, 3H), 1.46-1.28 (d, J=9.0 Hz, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=4)[CH:15]=3)[N:11]([C@H:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].O>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=4)[CH:15]=3)[N:11]([C@H:26]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc3cc(OC)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate (3.53 g, 6.48 mmol) was dissolved in MeOH-dioxane (1:1, 100 ml), and a solution of NaOH (1.2 g, excess)/water (10 ml) was added. The reaction was stirred at room temperature overnight. After concentrating the reaction mixture to 50 ml, it was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine 2× and dried over Na2SO4. Evaporation of solvent and vacuum drying gave 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoic acid as a white powder. NMR (500 MHz, CDCl3) δ: 1.97 (d, J=7.0 Hz, 3H); 3.95 (s, 3H); 5.61 (q, J=7.0 Hz, 1H); 6.66 (s, 1H); 7.17 (d, J=2.5 Hz, H); 7.21 (dd, J=2.5, 9.0 Hz, 1H); 7.29 (dd, J=1.6, 8.4 Hz, 1H); 7.31 (t, J=1.9 Hz, 1H); 7.32 (d, J=8.4 Hz, 2H); 7.63 (d, J=1.6 Hz, 1H); 7.67 (d, J=9.0 Hz, 1H); 7.77 (d, J=8.4 Hz, 1H); 7.80 (d, J=1.9 Hz, 2H); 8.05 (d, J=8.4 Hz, 2H).
Reaction SMILES: C1C[O:4]CC1.[CH2:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([F:25])[C:18]([F:24])=[CH:19][CH:20]=3)[O:15]2)[CH2:10][CH2:9]1)[CH3:7].C([Li])CCC.CCCCCC.OO>O.C(O)(=O)C>[CH2:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([F:25])[C:18]([F:24])=[C:19]([OH:4])[CH:20]=3)[O:15]2)[CH2:12][CH2:13]1)[CH3:7]
Reactant: C1CCOC1
Reactant: CC[C@H]1CC[C@H](C2CCc3ccc(F)c(F)c3O2)CC1
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC[C@H]1CC[C@H](C2CCc3cc(O)c(F)c(F)c3O2)CC1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
Into the THF (150 ml) solution of 2-(trans-4-ethylcyclohexyl)-7,8-difluorochroman (28 g), a 1.6 M butyllithium-hexane solution (65 ml) was added dropwise at −60° C., and stirred for 2 hours at −50° C. Into this, borate trimethyl (15 g) was added dropwise, stirred for 30 minutes, and warmed to 0° C. over 2 hours. Into this, acetic acid (10 ml) was added, and stirred for 20 minutes, to which 30% hydrogen peroxide aqueous solution (20 ml) was gradually added, and stirred for 1 hour. Into this, water (100 ml) was added, which was subjected to extraction using ethyl acetate, followed by concentration. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2-(trans-4-ethylcyclohexyl)-7,8-difluoro-6-hydroxychroman (28 g).
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10])[C:4](=[O:23])[O:3]1>CCO>[CH2:2]([O:3][C:4](=[O:23])[CH2:5][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 96 %

Procedure:
tert-Butyl (2S)-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)carbonyl]-1-pyrrolidinecarboxylate (85 g, 250 mmol) was dissolved in 500 mL absolute EtOH and refluxed for 3 h. Concentration provided the title compound as a light yellow oil (68.4 g, 240 mmol, 96%). 1H NMR (400 MHz, CDCl3, mixture of rotamers and keto/enol tautomers) δ 4.35 (m, 0.5H), 4.25 (m, 0.5H), 4.17 (m, 2H), 3.6–3.4 (m, 3H), 2.2–1.8 (m, 4H), 1.4 (m, 9H), 1.15 (m, 3H) ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.[O:26]=[C:27]1[C:36]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=2[NH:30][C:29]2[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([O:43][CH3:44])=[O:42])[C:28]1=2.[CH3:45][C:46]1([C:49](O)=[O:50])[CH2:48][CH2:47]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:45][C:46]1([C:49]([N:33]2[CH2:32][C:31]3[NH:30][C:29]4[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([O:43][CH3:44])=[O:42])[C:28]=4[C:27](=[O:26])[C:36]=3[CH2:35][CH2:34]2)=[O:50])[CH2:48][CH2:47]1
Reactant: CC1(C(=O)O)CC1
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C1(C)CC1)C3
Yield: 24.8 %

Procedure:
A solution of HATU (340 mg, 0.9 mmol) in DMF (2 ml) was added to a mixture of methyl 5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (200 mg, 0.77 mmol) from Example 13 (Step 2), 1-methylcyclopropanecarboxylic acid (102 mg, 1.02 mmol), diisopropylethylamine (0.5 mL, 5.09 mmol) and DMF (8 ml). The resultant mixture was stirred at ambient temperature for 8 hours. The DMF was evaporated and the residue was purified by pre-TLC to give methyl 2-(1-methylcyclopropanecarbonyl)-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (65 mg, 25%) as yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([CH:23]([CH2:26][CH3:27])[CH2:24][NH2:25])[CH3:22]>>[CH2:21]([CH:23]([CH2:26][CH3:27])[CH2:24][NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:22]
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CCC(CC)CN
Product: CCC(CC)CNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 68.4 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-ethylbutylamine (0.0186 g, 0.184 mmol) gives the title compound (0.0450 g, 68.6%): TOF MS ES+ 358.2 (M+H)+. HRMS calcd for C20II28N3O3 358.2131 (M+H)+, found 358.2127, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.6 min, 98.8% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]
Reactant: Nc1cnccn1
Reactant: COc1ccc([N+](=O)[O-])cc1N=C=O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)Nc1cnccn1

Procedure:
A mixture of 2-methoxy-5-nitrophenyl iso-cyanate (5.0 g, 25 mmol) and aminopyrazine (2.5 g, 26 mmol) in tetrahydrofuran (THF, 250 mL) was stirred at reflux for 24 hours. The product was precipitated from the cooled reaction mixture and was collected by filtration, washed with ethyl acetate, and dried in vacuo (4.3 g, 57%). 1H NMR (300 MHz, d6-DMSO) (mixture of rotamers) δ: 10.38 (br, s, 1H), 10.27 (s, 1H), 9.39, 8.88 (2 singlets, 1H), 9.10(d, 1H), 8.33 (s, 1H), 8.26 (d, 1H), 7.98-8.25 (m, 1H), 7.97-7.84 (m, 1H), 4.05, 4.03 (2 singlets, 77:28 ratio, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:22]([O:24]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[CH:9][CH:8]=1.[C:30]1([C:36]2[N:37]=[C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[S:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:22]([N:44]2[CH2:45][CH2:46][N:41]([C:38]3[S:39][CH:40]=[C:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:37]=3)[CH2:42][CH2:43]2)=[O:24])=[CH:11][CH:12]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C1CCCN1c1ccc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc(N2CCCC2=O)cc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 68.4 %

Procedure:
A solution of bis(2,2,2-trichloroethyl) [4-(2-oxopyrrolidin-1-yl)phenyl]imidodicarbonate (200 mg, 0.379 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (196 mg, 0.758 mmol), diisopropylethylamine (0.132 ml, 0.758 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 116 mg (68.2%) of the desired product as a solid.
Reaction SMILES: C(OC(=O)[N:7]([CH:27]([CH3:29])[CH3:28])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>C(O)CCC>[CH:27]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:28])[CH3:29]
Reactant: Nc1ccccc1
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1nccn2c(-c3ccnc(S(C)(=O)=O)n3)cnc12
Agent: Cl
Solvent: CCCCO
Product: CC(C)Nc1nccn2c(-c3ccnc(Nc4ccccc4)n3)cnc12

Procedure:
To isopropyl-[3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (117 mg, 0.27 mmol) (from Example 11 supra) was added aniline (38 μL, 0.42 mmol) in nBuOH (3 mL) followed by conc.HCl (38 μL, 0.46 mmol) and the reaction was shaken at 95° C. overnight. After this time the reaction was concentrated to dryness, dissolved in DMSO (1.8 mL) and then purified by preparative HPLC to give isopropyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine. (Yield 27.3 mg, 29%). LC-MS: [M+H]+ 346.3.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)CCCC2
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2ccccc2c1
Yield: 67 %

Procedure:
Tetralin (1,2,3,4-tetrahydronaphthalene) reacts quantitatively) with water under the standard condition to give 22% benzene, 6% toluene, 67% naphthalene, and the rest to gases. The exit gas composition was 77% H2, 19% CO2, 3% CO, and 2% CH4. By raising the reaction temperature to 550° C., the yield of benzene increases to 49%, while the amount of naphthalene decreases to 10%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O>>[CH2:1]([N:8]1[CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Reactant: NCCNCc1ccccc1
Product: Clc1ccc(C2CCN(Cc3ccccc3)CCN2)cc1

Procedure:
This compound was prepared by the method of preparation 2 starting from N-benzylethylenediamine but using commercially available 3-chloro-1-(4-chlorophenyl)propan-1-one. LRMS: APCl+ m/z 300 [MH+].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[Cl:36][C:37]1[N:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:36][C:37]1[N:42]=[C:41]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:15][C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=5)=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[CH:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CC1(C)OB(c2cccc(Cl)n2)OC1(C)C
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 105 °C
Yield: 90.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (300 mg, 0.487 mmol) and 6-chloropyridine-2-boronic acid pinacol ester (175 mg, 0.730 mmol) in p-dioxane/H2O (4:1, 5 mL) followed by bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (17.23 mg, 0.024 mmol) and potassium phosphate (310 mg, 1.460 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 30 min. The mixture was diluted with DCM and washed with H2O. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-20% EtOAc in DCM) to give 5-(3-(6-chloropyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (265 mg, 0.440 mmol, 90%) as a yellow solid. MS (ESI, pos. ion) m/z: 602 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 8.73 (1H, d, J=1.4 Hz), 8.14 (1H, s), 8.05 (1H, d, J=8.8 Hz), 7.92 (1H, dd, J=8.7, 1.7 Hz), 7.81 (2H, d, J=8.2 Hz), 7.68-7.75 (1H, m), 7.59-7.66 (1H, m), 7.33 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=3.7 Hz), 6.90 (2H, d, J=8.8 Hz), 4.54 (2H, s), 3.81 (3H, s), 2.35 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CCCCCC1CCC(C=Cc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCC1CCC(CCc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Yield: 87.9 %

Procedure:
6.9 g (17.4 mmol) of 4-{4-[2-(4-pentyl-cyclohexyl)-vinyl]-phenyl}cyclohexane carboxylic acid methyl ester produced in Example 6-1 was dissolved in a mixture of toluene and ethanol (1:1 by volume %). 0.4 g of Pd/C was added to 200 mL of the resultant solution and reacted in hydrogenation reactor for 12 hours. After reaction, Pd/C was removed by filtration, concentrated under reduced pressure and recrystallized from chloroform and ethanol to obtain 6.1 g (88%) of 4-{4-[2-(4-pentyl-cyclohexyl)-ethyl]-phenyl}-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]CBr>>[Br:15][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:1]=[O:8]
Reactant: O=Cc1ccccc1
Reactant: BrCBr
Agent: ClBr
Agent: [Al+3]
Agent: [Cl-]
Product: O=Cc1cccc(Br)c1

Procedure:
A process which comprises reacting one molar proportion of benzaldehyde with about 0.9-1.2 molar proportions of bromine chloride in the presence of about 1.1-2.2 molar proportions of aluminum chloride and about 0.3-0.9 mol of dibromomethane per mol of aluminum chloride under substantially anhydrous conditions at a temperature in the range of about 40°-95° C. so as to form 3-bromobenzaldehyde, the components of the reaction mixture being combined by gradually adding the bromine chloride to a dibromomethane slurry of the benzaldehyde and aluminum chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[C:33]#[CH:34].CN(C=O)C>N(CC)CC.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][N:35]4[CH2:36][CH2:37][S:38](=[O:42])(=[O:41])[CH2:39][CH2:40]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN1CCS(=O)(=O)CC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCN3CCS(=O)(=O)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-propargylthiomorpholine-1,1-dioxide (103.8 mg). Anhydrous DMF (18 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (4L), and 2.5% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined, concentrated, and further purified by HPLC. The product is recrystallized from hot acetonitrile to afford 86.1 mg (27%) of the desired product as a white solid.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:5][C:6]([C:10](=[O:12])[CH3:11])=[C:7]([CH3:9])[N:8]=1>C(O)(=O)C>[CH3:3][C:4]1[S:5][C:6]([C:10](=[O:12])[CH2:11][Br:1])=[C:7]([CH3:9])[N:8]=1
Reactant: BrBr
Reactant: CC(=O)c1sc(C)nc1C
Solvent: CC(=O)O
Product: Cc1nc(C)c(C(=O)CBr)s1
Reaction time: 1 h

Procedure:
A solution of 20.8 g (0.13 mol) of bromine in 50 ml of glacial acetic acid is slowly added dropwise to a solution of 20.2 g (0.13 mol) of 2,4-dimethyl-5-acetyl-thiazole in glacial acetic acid, heated to reflux. After 1 hour, the mixture is evaporated to dryness, the residue is dissolved in water, and the solution is neutralised with sodium carbonate solution. The mixture is then extracted several times with methylene chloride, and the organic phase is dried and concentrated. The oil which was obtained in this way was used for further reactions without further purification.
Reaction SMILES: [Gd:1].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na+].[Cl-].[C:24]([O-:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([O-:34])=[O:33])([C:28]([O-:30])=[O:29])[OH:27].[Na+].[Na+].[Na+]>>[C:24]([O-:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([O-:34])=[O:33])([C:28]([O-:30])=[O:29])[OH:27].[Gd+3:1]
Reactant: [Gd]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Cl-]
Product: [Gd+3]

Procedure:
Thousands of Gadolinium ions may be incorporated onto silica nanoparticles surface via coordination with EDTA chelators presented on EDTA-SiO2 particle surface. Gadolinium Citrate solution was prepared in 10 mM Et3NHOAc (pH 7.0 with 0.15M NaCl) as mentioned: 0.6 M GdCl3 aqueous solution and 0.6 M sodium citrate solution were mixed in 1:1 volume ratio. Brief vortex of the mixture afforded 0.3 M Gadolinium Citrate solution. To a 20 mL scintillation vial equipped with a Teflon-coated stir bar was added 5 mL 10 mM Et3NHOAc (pH 7.0 with 0.15M NaCl) buffer and 1.67 mL of 0.3 M Gadolinium Citrate solution. Then 5 mL of EDTA-SiO2 (0.6% EDTA-SiO2 in deionized H2O by wt %) was added to the reaction mixture. The solution was stirred under room temperature for 18 hours. Reaction mixture stayed clear. The Gd solution was purified by dialyzing against DI H2O overnight in a SnakeSkin (10,000 MWCO) dialysis tube. Dialyzed solution was recovered and stored at room temperature on shelf. No sign of aggregation was observed (based on DLS) after at least one month.