Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C@H:19]1[C@@H:24](OS(C)(=O)=O)[CH2:23][CH2:22][N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:20]1.C(Cl)Cl>CN(C=O)C.CCOC(C)=O>[F:18][C@H:19]1[C@H:24]([O:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH2:23][CH2:22][N:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:20]1
Reactant: Oc1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc3cccnc23)[C@H](F)C1
Temperature: 100 °C
Reaction time: 20 h
Yield: 8.4 %

Procedure:
To a solution of quinolin-8-ol (3.50 g, 24.1 mmol) in 60 mL DMF was added cesium carbonate (23.6 g, 72.3 mmol), followed by (cis)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (8.24 g, 27.7 mmol). The reaction mixture was heated in a 100° C. sand bath and stirred 20 hours. The reaction mixture was cooled to ambient temperature, filtered through GF/F paper topped with compressed Celite, rinsed with DMF, and concentrated. The crude was purified on silica gel (Biotage 40M, 9:1 DCM:EtOAc until the product eluted, then 2:1 DCM:EtOAc) to give (trans)-tert-butyl 3-fluoro-4-(quinolin-8-yloxy)piperidine-1-carboxylate (0.701 g, 2.02 mmol, 42% yield). LC/MS ESI (+) m/z 347 (M+1) detected.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=2[O:34][CH3:35])[N:3]=1.[NH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:45]=1[C:44](=[O:46])[N:43]([CH3:47])[CH2:42]2>>[CH3:35][O:34][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:36][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:45]=2[C:44](=[O:46])[N:43]([CH3:47])[CH2:42]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[O:19][CH2:20][C:21]([F:24])([F:23])[F:22]
Reactant: CN1Cc2cccc(N)c2C1=O
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Product: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1Nc1ncc(C(F)(F)F)c(Nc2cccc3c2C(=O)N(C)C3)n1

Procedure:
The title compound was prepared according to the procedure for Example 102 using bis(2,2,2-trifluoroethyl) (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 124A, 67.0 mg, 0.119 mmol) and 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (Preparation XXXVIII, 26.9 mg, 0.166 mmol). The crude product was adsorbed onto a pre-filled solid loading cartridge and purified using the Teledyne/ISCO Combiflash system eluting with 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo. The material was further purified by MDP (under basic conditions; ammonium bicarbonate buffer, pH 9), which afforded the title material as an off-white solid, 54.8 mg (64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H), 9.13 (s, 1H), 8.40 (s, 1H), 8.37 (br s, 1H), 7.49 (br d, J=7.1 Hz, 1H), 7.37 (br t, J=7.1 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.60-4.74 (m, 4H), 4.45 (s, 2H), 3.74 (s, 3H), 3.61 (d, J=22.2 Hz, 2H), 3.06 (s, 3H). MS (ES+): m/z 688.08 (100) [MH+]. HPLC: tR=3.72 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([Li])CCC.[Br-].[PH4+].[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:15][C:14]2=[O:25])(=O)[CH3:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:21]([C:16]1[NH:17][C:18]2[C:13]([C:14](=[O:25])[N:15]=1)=[CH:12][C:11]([C:8]([CH3:1])=[CH2:9])=[CH:20][CH:19]=2)[CH2:22][CH2:23][CH3:24]
Reactant: [Li]CCCC
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [PH4+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
To a suspension of 3.66 g of methyltriphenylphosphonium bromide in 30 ml of dry tetrahydrofuran, cooled to -78° C. is added dropwise 5.9 ml of a 1.73M solution of n-butyllithium in hexanes. Following complete addition, the reaction mixture is allowed to warm to room temperature and stirred for 15 minutes, until all the phosphonium bromide is dissolved. The reaction mixture is then recooled to -78° C. and a suspension of 6-acetyl-2-butyl-4(1H)-quinazolinone in 15 ml of dry tetrahydrofuran is added. The reaction is allowed to warm to room temperature and stirred for 24 hours followed by quenching with saturated ammonium chloride solution. After diluting with 10 ml of water, the aqueous layer is extracted with chloroform and the combined organics dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:2 ethyl acetate-hexanes to give 0.23 g of the desired product as a white solid. CI MASS SPEC 243(MH+ ).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[N:12][CH:13]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(C)(C)C>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:14][C:9]2[C:8]([Cl:7])=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncncc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Clc1cncnc1NCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
2.1 g (19 mmol) of potassium tert-butylate are added to a suspension of 2.2 g (17.2 mmol) of 5-chloro-pyrimidin-4-ylamine in tert-butanol (50 ml) and the temperature is kept at 60° C. After stirring for 1 h, a solution of 4.1 g (17.2 mmol) of 4-benzyloxy-benzyl chloride in tert-butanol (40 ml) is added dropwise and the reaction mixture is stirred at this temperature for 1 h. The reaction mixture is cooled to room temperature and poured into water (300 ml). The precipitate is filtered off and the filtrate is extracted with ethyl acetate (2×200 ml). The combined organic layers are dried with magnesium sulphate and concentrated in vacuo. The residue is purified by chromatography on silica gel (toluene/dioxane=6:1) to yield 2.0 g (37%) of the title compound as a beige powder of m.p. 95°-100° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[CH3:12])=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>C(OCC)C>[Br-:1].[CH3:13][NH+:14]1[CH:18]=[CH:17][N:16]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=2[CH3:12])=[O:4])[CH2:15]1
Reactant: Cn1ccnc1
Reactant: Cc1ccc(C(=O)CBr)c(C)c1
Solvent: CCOCC
Product: Cc1ccc(C(=O)CN2C=C[NH+](C)C2)c(C)c1
Product: [Br-]
Yield: 50.8 %

Procedure:
A solution of 4.76 g (0.021 mol) of 1-bromo-2-(2,4-dimethylphenyl)-2-oxoethane and 1.76 g (0.021 mol) of 1-methylimidazole in 50 ml of diethyl ether was stirred at room temperature for approximately 21 hours. The reaction solvent was decanted and the residue was washed with diethyl ether. The residue was recrystallized from acetonitrile/ethyl acetate to afford 3.32 g of the title product as white crystals. (51% yield) mp=179°-181° C.
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[ClH:21].[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([Cl:1])=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: O=S(Cl)Cl
Agent: Cl
Product: O=C(Cl)c1c2ccccc2nc2ccccc12
Temperature: 110 °C

Procedure:
A mixture of acridine-9-carboxylic acid hydrochloride (74 mg, 0.33 mmol) in thionyl chloride (3 ml, 41.1 mmol) was refluxed at 110° C. under nitrogen for 2 hours. After cooling, the solution was evaporated under reduced pressure to dryness. The solid was washed with anhydrous diethyl ether (5 ml) to give acridine-9-carbonyl chloride hydrochloride. This acid chloride was dissolved in anhydrous pyridine (4 ml), followed by addition of benzyl 3,5-diisopropyl-4-hydroxy-benzoate (102 mg, 0.33 mmol) and 4-N,N-dimethylamino-pyridine (16 mg, 0.13 mmol). After 16 hours of stirring at 25° C. under nitrogen, the solution was evaporated under reduced pressure to dryness. The residue was purified on a Chromatotron plate (1 mm silica gel) by elution with 20% diethyl ether/hexane to yield (4 -benzyloxycarbonyl-2,6-diisopropyl)phenyl acridine-9-carboxylate (64 mg, 38%). Rf 0.6 (silica gel, 20% ethyl acetate/toluene). MS(EI): m/z 517(M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]1([CH2:41][CH2:42]CO)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:42][CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:18][CH:17]=1
Reactant: OCCCc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCc4ccccc4)cc3)c2cc1OC
Yield: 69.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-phenyl-1-propanol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric-acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (54 mg, yield 64%).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].C(=O)(OC)OC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].Cl>O.C(O)(C)(C)C>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH:21]1[O:25][C:2](=[O:4])[NH:24][C:22]1=[O:23]
Reactant: NC(=O)C(O)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COC(=O)OC
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1NC(=O)C(c2c(Cl)cccc2Cl)O1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (5.16 g., 0.046 mole) was dissolved in 60 ml. of tert-butanol. Dimethyl carbonate (4.14 g., 0.046 mole) and then 2-(2,6-dichlorophenyl)-2-hydroxyacetamide (5 g., 0.023 mole) were added. The suspension was heated at reflux for 2 hours and cooled to room temperature. Hydrochloric acid (46 ml. of 1N) and then 100 ml. of water were added, and the mixture extracted with three portions of methylene chloride. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Recrystallization of the residue from toluene gave purified 5-(2,6-dichlorophenyl)oxazolidine-2,4-dione (3.15 g., 50 %; m.p. 151°-153° C.), ir (KBr) 1818, 1739, 1724, 1434, 1377 cm-1.
Reaction SMILES: [BH4-].[Li+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13](OC)=[O:14])=[CH:9][CH:10]=2)[NH:5]1.O.Cl>O1CCCC1>[OH:14][CH2:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4](=[O:3])[NH:5]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2ccc(CO)cc2N1
Temperature: 50 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
Lithium borohydride (228 mg) was added to a suspension of methyl 2-oxoindolin-6-carboxylate (1.0 g) in tetrahydrofuran (10 ml) under ice-cooling and the mixture was stirred at 50° C. for 3 hours. Lithium borohydride (456 mg) was further added and the reaction mixture was stirred at 50° C. for 15 hours. Water was added to the reaction mixture under ice-cooling and the mixture was acidified with addition of conc. hydrochloric acid. It was extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The resulted residue was triturated in methanol to give 6-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (172 mg) as a colorless powder. The mother liquid was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1 to ethyl acetate) to give the same (242 mg) as a colorless powder.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]2[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=2[O:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][NH:22]2)[CH:12]=[CH:13][CH:14]=1.CI>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]2[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=2[O:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:1])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(CCc2ccccc2OC[C@@H]2CCCN2)c1
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(CCc2ccccc2OC[C@@H]2CCCN2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.5 %

Procedure:
130 mg of potassium carbonate were added to a solution of 500 mg of (S)-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared as described in Example 57(b)] in 5 ml of dimethylacetamide, and the resulting mixture was stirred at room temperature for 5 minutes, after which 288 mg of methyl iodide were added. The reaction mixture was then stirred at room temperature for 5 minutes, after which it was diluted with ethyl acetate. The diluted solution was then washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 320 mg (yield 61%) of the title compound as a colorless oil.
Reaction SMILES: C(O[C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19]#[C:20][CH2:21]Br)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[C:40]([O:43][CH2:44]C)(=[O:42])[CH3:41]>CN(C)C=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:41][C:40]([O:43][CH3:44])=[O:42])[CH:6]=2)=[CH:12][C:13]=1[C:19]#[C:20][CH2:21][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:32])([F:33])[F:23])=[CH:30][CH:29]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(C)=O
Reactant: COc1ccc(-c2cccc(OC(C)=O)c2)cc1C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(C#CCOc3ccc(C(F)(F)F)cc3)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6.8 mg of Methyl [3′-(3-bromo-1-propynyl)-4′-methoxybiphenyl-3-yl acetate was dissolved in 0.2 ml of N,N-dimethylformamide, 10 mg of 4-trifluoromethylphenol and 10 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated to give methyl {4′-methoxy-3′-[3-(4-trifluoromethylphenoxy)-1-propynyl]biphenyl-3-yl}acetate. This product was dissolved in 0.4 ml of ethanol, then 0.1 ml of 5N aqueous sodium hydroxide was added thereto, and the mixture was stirred overnight at room temperature. 1N hydrochloric acid was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography to give 4.89 mg of the title compound.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([C:29](O)([CH3:31])[CH3:30])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:33])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(S(F)(F)[F:40])CC)C.C(#N)C.O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:28]([C:29]([F:40])([CH3:30])[CH3:31])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:33])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(C)(O)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Reactant: CCN(CC)S(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(2-hydroxypropan-2-yl)benzamide (0.067 g, 0.14 mmol) in anhydrous dichloromethane (10 mL) was added diethylaminosulfur trifluoride (22 μL, 0.17 mmol) at −78° C. The reaction mixture was stirred for 2 hours at −78° C. and then quenched by addition of saturated sodium bicarbonate solution (5 mL). The mixture was allowed to warm to ambient temperature and diluted with dichloromethane (50 mL). The organic phase was washed with brine (5 mL), dried over anhydrous magnesium sulfate, and filtered. The residue obtained after concentration of the filtrate in vacuo was purified by silica gel column chromatography using 0-20% ethyl acetate in hexanes as eluent to afford a beige solid. Lyophilization from acetonitrile and water (2 mL, 1:1) gave the title compound as colorless solid (0.012 g, 18%): 1H NMR (300 MHz, DMSO-d6) 11.74 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.11 (d, J=12.7 Hz, 1H), 4.05 (t, J=7.6 Hz, 4H), 3.69 (s, 2H), 2.23-2.11 (m, 2H), 2.04-1.97 (m, 3H), 1.79-1.61 (m, 18H); 19F NMR (282 MHz, CDCl3) 6-109.8 (s, 1F), −130.0 (s, 1F); MS (ES−) m/z 481.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1>C1COCC1.C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(N)cc2)cc1

Procedure:
The above nitro compound was hydrogenated in THF-ethanol in the presence of Raney nickel catalyst, providing 4-[(4-methoxyphenyl)methoxy]benzenamine, mp 118°-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]
Reactant: CC(C)=CCBr
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.30 g (102.0 mmol) of 2-bromothiophenol, 160 ml of DMF and 15.50 g (112.0 mmol) of potassium carbonate are introduced into a three-necked flask. 13 ml (112.0 mmol) of 1-bromo-3-methyl-2-butene are added dropwise and the mixture is stirred at room temperature for two hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling, washed with water, dried over magnesium sulphate and evaporated. 26.00 g (99%) of the expected compound are collected in the form of an orange-coloured oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[H-].[Na+].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(CCN3CCCC3)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 2, 9.10 g, 31 mmol) in tetrahydrofuran (100 mL) cooled to 0° C., were added sodium hydride (12.4 g, 310 mmol) and p-toluenesulfonyl chloride (6.10 g, 32 mmol). The resulting mixture was stirred at room temperature for 3 h, poured into water (200 mL) and extracted into ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and then poured onto a silica gel column which was eluted with ethyl acetate followed by methanol. The title compound was obtained as a yellow syrup (11.7 g, 90%).
Reaction SMILES: OCCNC([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:8]([C:10]1[S:14][C:13]([C:15]([O:17]C)=O)=[CH:12][CH:11]=1)=[O:9])=O.[OH2:26].[NH2:27][NH2:28]>C(O)C>[NH:27]([C:15]([C:13]1[S:14][C:10]([C:8]([NH:7][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:8](=[O:9])[NH:7][CH2:19][CH2:20][OH:26])=[CH:24][CH:25]=2)=[O:9])=[CH:11][CH:12]=1)=[O:17])[NH2:28]
Reactant: COC(=O)c1ccc(C(=O)N(Cc2ccccc2)C(=O)NCCO)s1
Reactant: O
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NCCO)cc2)s1
Yield: 185.8 %

Procedure:
0.73 g (2.02 mmol) of methyl 5-[-(2-hydroxyethylcarbamoyl)benzylcarbamoyl]thiophene-2-carboxylate in 12 mL of ethanol was mixed with 1.67 mL (34.43 mmol) of hydrazine monohydrate and heated under reflux for 9 hours. The reaction solution was cooled with ice, and the precipitated solid was collected by filtration, washed with ethanol and dried under reduced pressure to obtain the desired product (0.68 g, yield 93%).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:7]=1[CH2:8][C:9](=[CH2:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[CH2:24]([N:31]1[C:2]2[N:3]=[N:4][C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:6][C:7]=2[CH2:8][CH:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:17]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(Cc1cc(-c2ccccc2)nnc1Br)C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)C1Cc2cc(-c3ccccc3)nnc2N(Cc2ccccc2)C1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a stirred solution of compound 5E, (0.140 g, 0.37 mmol) in 1.5 mL of isopropanol at room temperature under argon was added (in one portion) benzylamine (0.055 mL, 0.50 mmol). After 15 h, the reaction mixture was heated to 65° C. for 4 h and then to 85° C. for 15 h. The reaction mixture was then cooled to room temperature and the solvent removed at reduced pressure. The residue was dissolved in EtOAc and washed once with saturated sodium bicarbonate solution. The organic extract was dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by silica gel chromatography (1:9 Ether/CH2Cl2) provided the title compound, tert-butyl 8-benzyl-3-phenyl-5,6,7,8-tetrahydropyrido[2,3-c]pyridazine-6-carboxylate, as a light yellow solid (0.084 g, 57%). MS [M+H]+: found 402.