Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[SH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Reactant: Sc1ccccn1
Product: CCOC(=O)[C@@H]1CC(Sc2ccccn2)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 2-mercaptopyridine. Light brown semi-solid (74%). MS (EI): 385.3 (M+H)+.
Reaction SMILES: C(C(C)=O)C(C)C.[C:8]1([CH:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N+:39]([O-:41])=[O:40])[CH2:25][CH2:24]1>C(N(CC)CC)C>[C:8]1([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-:41])=[O:40])[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reaction time: 15 h
Yield: 76 %

Procedure:
Into 270 ml of methyl isobutyl ketone were dissolved 32.1 g of diphenylmethyl bromide, 28.0 g of 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 30.4 g of triethylamine. The resultant solution was heated under reflux with stirring for 15 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with methanol-chloroform (1:50) by silica gel column chromatography to give 33.9 g of oily 4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH2:23][N:24]([CH2:32][C@@H:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=3)[O:34][Si](C(C)(C)C)(C)C)C(OC(C)(C)C)=O)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]>Cl.O1CCOCC1>[ClH:48].[ClH:48].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH2:23][NH:24][CH2:32][C@@H:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=3)[OH:34])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)cc1C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)cc1C(=O)OC

Procedure:
Assay Found: C 55.03; H 5.36; N 5.04%; C26H27Cl1N2O5.0.64H2O requires C 55.04; H 5.38; N 4.94%; from (R)-3′-[[2-[[2-(3-chlorophenyl)-2-[[(tert-butyl)dimethylsilyl]oxy]ethyl][(tert-butoxy)carbonyl]amino]ethyl]amino]-[1,1′-biphenyl]-3,4-dicarboxylic acid dimethyl ester (1.1 g) in 4 N hydrochloric acid in dioxane (10 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[SH:11].[C:12]([C:14]1[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][CH:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[S:11][C:12]([C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][CH:15]=3)=[N:13][C:5](=[O:7])[C:4]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Reactant: Cc1cccc(C(=O)O)c1S
Solvent: c1ccncc1
Product: Cc1cccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc12

Procedure:
A mixture of 3-methylthiosalicylic acid (2.52 g, 15 mmol), tert-butyl 3-(6-cyano-2-pyridyl)propanoate (2.32 g, 10 mmol) and pyridine (30 ml) was refluxed under nitrogen atmosphere for 20 hrs and concentrated under reduced pressure. The residue was subjected to a silica gel (100 g) column chromatography. The titled compound (2.79 g, 73%) was given from the fractions eluted with hexane-ethyl acetate (2:1, v/v), which were recrystallized from ethyl acetate-isopropyl ether.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=3)[CH2:28][CH2:29]2)[N:19]=1
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Reactant: COc1ccnc(N2CCNCC2)n1
Product: COc1ccnc(N2CCN(Cc3ccc(C(C)(C)NC(C)=O)cc3)CC2)n1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-methoxypyrimidin-2-yl)piperazine obtained in Example 98(2) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=160-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[C:5](OC)=[O:6].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:22])[CH3:23])[CH:14]=1)[CH2:5][OH:6]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.8 %

Procedure:
Methyl 3,5-dichloro-4-(4-methoxy-3-isopropyl-phenoxy)benzoate (Example 5a) (3.0 g) was treated with a 1 M solution of diisobutyl aluminium hydride (DIBAL) in THF (32.5 ml) at 0° C. and then warmed to room temperature and stirred overnight. The reaction mixture was poured into an ice-cold 1 M HCl solution and extracted with ethyl acetate three times. The organic layer was washed (brine), dried, filtered and concentrated to dryness affording 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzylalcohol (3.21 g, 100%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>CN(C)C=O>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-ol (0.23 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.11 g) and bromoacetic acid methyl ester (0.075 mL) was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure and the residue diluted with ethyl acetate and this mixture was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:1 by volume) gave title compound, 0.11 g.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[CH:45]=[CH:46][N:47]=[CH:48]2.O1CCOCC1.Cl>ClCCl.CCOCC.[I+].[Cu+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:48]1[C:49]2[C:44](=[CH:43][CH:52]=[CH:51][C:50]=2[C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=2)[CH:45]=[CH:46][N:47]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Brc1cccc2cnccc12
Agent: [Cu+]
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cccc5ccncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 7.8 %

Procedure:
A microwave vessel was charged with 2-[4-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-isobutyramide (0.200 g, 0.288 mmol), 5-bromoisoquinoline (0.072 g, 0.346 mmol), copper(I) iodine (0.066 g, 0.346 mmol), palladium tetrakis(triphenylphosphine) (0.033 g, 0.029 mmol) and dioxane (4 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 140° C. under microwave irradiation for 20 min. The reaction mixture was cooled to room temperature and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 0 to 15% of a 9:1 MeOH:NH4OH mixture in dichloromethane) to give a yellow residue. This residue was dissolved in dichloromethane then 1 N HCl in ether (0.2 mL) added dropwise. The resulting precipitate was collected by filtration to furnish 135 (0.012 g, 6%) as a pale yellow powder and as a tetrahydrochloride salt. MS m/e 532 [M+H]+; 1H NMR (300 MHz, 360 K, DMSO-d6) δ ppm 1.49 (s, 6 H) 2.96-3.33 (m, 8 H) 3.79-3.91 (m, 4 H) 3.97-4.09 (m, 4 H) 4.22 (br. s., 2 H) 6.00 (br. s., 2 H) 7.65 (s, 1 H) 8.06-8.18 (m, 1 H) 8.23-8.35 (m, 2 H) 8.54 (d, J=7.5 Hz, 1 H) 8.68 (br. s., 1 H) 10.57 (br. s., 1 H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][O:30][C:31]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=[O:34]>>[CH:33]([C:32]1[C:31]([O:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])=[C:38]([C:2]2[C:16]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)[CH:37]=[CH:36][CH:35]=1)=[O:34]
Reactant: COCCOCOc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1Br
Product: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1-c1cccc(C=O)c1OCOCCOC

Procedure:
Proceeding as in Reference 19, but substituting tert-butyl [3-bromo-4-(2-methoxyethoxymethoxy)-benzyl]carbamate (2.3 g, 5.9 mmol) and 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (60 mL, 0.1 M in toluene), gave tert-butyl [3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]carbamate (2.96 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][NH:8][C:7]=2[CH:11]=1)#[N:2].[OH-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][N:8]1[C:7]2[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[N:10]=[CH:9]1
Reactant: N#Cc1ccc2nc[nH]c2c1
Reactant: ClCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: N#Cc1ccc2ncn(CCCCCl)c2c1
Temperature: 60 °C
Yield: 62.9 %

Procedure:
6-cyano-1H-benzimidazole (14.3 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Post treatment was performed based on common method one for synthesis. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 14.7 g of 1-(4-chlorobutyl)-6-cyano-1H-benzimidazole, with a yield of 63.1%.
Reaction SMILES: [H-].[Na+].P([O-])([O-])(O[CH:6]([CH2:9][CH3:10])[C:7]#[N:8])=O.CC([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=O>C1COCC1>[CH3:27][O:26][C:18]1[CH:17]=[C:16]([C:9]([CH3:10])=[CH:6][C:7]#[N:8])[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[O:24][CH3:25]
Reactant: CCC(C#N)OP(=O)([O-])[O-]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(C)=CC#N)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a slurry of 60% NaH (1.46 g, 61.1 mmol) in THF at 0° C. was added 10.0 g (56.4 mmol) of ethyl(cyanomethyl) phosphate. A solution of 9.88 g (47.0 mmol) of 3,4,5-trimethoxyacetophenone in THF was added precipitating a yellow solid. The mixture was stirred at room temperature for 30 minutes, quenched with water, and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4), and evaporated in vacuo to afford 9.32 g (85%) of 16 as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:21]CC4C=CC=CC=4)=[C:17]([Cl:20])[CH:18]=3)[C:13]([C:29]#[N:30])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([Cl:20])[CH:18]=3)[C:13]([C:29]#[N:30])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OCc4ccccc4)c(Cl)cc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(O)c(Cl)cc32)cc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of 4-(5-benzyloxy-6-chloro-3-cyanoindol-1-yl)benzoic acid ethyl ester (0.310 g) in dichloromethane (7 mL) was added boron tribromide (1 mol/L dichloromethane solution) (0.860 mL) under ice cooling, and this mixture was stirred at the same temperature for 1 hour. To this reaction mixture was added water, this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. This filtrate was removed under reduced pressure. The residue was washed with diethyl ether to give the title compound (0.181 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][C:3]1([CH3:19])[CH3:18]>[Pd].CO>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH3:19])[CH3:18]
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CCC1N
Agent: [Pd]
Solvent: CO
Product: CC1(C)CNCCC1N
Temperature: 30 °C
Reaction time: 6 h

Procedure:
A mixture of 10% palladium on carbon (7.5 g) and (−)-4-amino-1-benzyloxycarbonyl-3,3-dimethylpiperidine (cf. Preparation 19, Step 4, 50 g, 191.0 mmol) in methanol (500 ml) was stirred under hydrogen atmosphere (30 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with 100 ml methanol and filtrate was concentrated to dryness to afford (−)-4-amino-3,3-dimethylpiperidine, which was further purified by vacuum distillation to give 16.8 (71%) titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH:15]=[CH:14][C:13]=2[CH3:26])=[CH:8][CH:7]=1)=[O:5])C>C1COCC1.[OH-].[Na+]>[CH3:26][C:13]1[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[O:20])=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)c3cccs3)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1ccc(C(=O)O)cc1

Procedure:
2′-Methyl-5′-[(thiophene-2-carbonyl)-amino]-biphenyl-4-carboxylic acid ethyl ester (425 mg) in THF (10 ml) and sodium hydroxide (1M, 20 ml) was heated to reflux for 4 h. The solvent was then evaporated and the residue acidified. The resulting precipitate was collected by filtration and dried (321 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH2:18]1[NH:23][CH2:22][CH2:21][N:20]2[CH2:24][CH2:25][CH2:26][CH:19]12.C(N(C(C)C)CC)(C)C.Cl>C(#N)C.ClCCl.C(OCC)C>[C:12]1([C:4]2[CH:3]=[C:2]([N:23]3[CH2:22][CH2:21][N:20]4[CH2:24][CH2:25][CH2:26][CH:19]4[CH2:18]3)[N:7]=[N:6][C:5]=2[C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1nnc(Cl)cc1-c1ccccc1
Reactant: C1CC2CNCCN2C1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: FC(F)(F)c1nnc(N2CCN3CCCC3C2)cc1-c1ccccc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A mixture of 6-chloro-4-phenyl-3-trifluoromethyl-pyridazine (D3) (0.10 g, 0.39 mmol), octahydro-pyrrolo[1,2-a]pyrazine, racemic mixture, (0.053 g, 0.42 mmol) and diisopropylethylamine (0.103 ml, 0.585 mmol) in acetonitrile (3 ml) was stirred at 150° C. for 30 min., under microwave irradiation. The reaction mixture was then diluted with dichloromethane (25 ml) and extracted with a saturated solution of sodium carbonate (12 ml). The organic layers were separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; 0-2.5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The residue was precipitated from acetonitrile/heptane. The product obtained was treated with a solution of hydrochloric acid in diethyl ether (2M) to yield the corresponding salt E5 (0.081 g, 54%) as a white solid. C18H19F3N4.HCl; free base requires 348; Found 349 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]1=2.[OH:25][C:26]1[CH:34]=[C:33](I)[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29].[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[OH:17][CH:14]([C:6]1[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]2[C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[C:15]#[C:16][C:33]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:25])[CH:34]=1
Reactant: O=C(O)c1ccc(I)cc1O
Reactant: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCCOc1cc(C(O)C#Cc2ccc(C(=O)O)c(O)c2)cc2c1C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
200 mg (0.6 mmol) of 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol (Example 2b) and 175 mg (0.4 mmol) of 2-hydroxy-4-iodobenzoic acid are dissolved in 5 mL of DMF and 2 mL of triethylamine. 10 mg of copper iodide and 20 mg of dichloropalladiumbis(triphenylphosphine) are added, and the reaction medium is stirred at 50° C. for 2 hours 30 minutes. The reaction medium is poured into ammonium chloride solution and extracted with ethyl acetate. The residue is purified on a column of silica (eluent: 5/5 heptane/EtOAc). The desired product is obtained in the form of a yellowish powder (m=80 mg; yield=42%; m.p.=120° C.) 1H NMR (DMSO D6): 1.13 (t, J=7.0 Hz, 3H); 1.24 (s, 6H); 1.36 (s, 6H); 1.56-1.61 (m, 4H); 3.52 (q, J=7.0 Hz, 2H); 3.76 (m, 2H); 4.07 (m, 2H); 5.51 (s, 1H); 6.15 (bs, 1H); 6.89 (s, 1H); 6.97 (m, 2H); 7.11 (s, 1H); 7.77-7.79 (m, 1H), 11.5 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]3[C:36]4[C:31](=[C:32]([C:38](F)(F)F)[CH:33]=[CH:34][C:35]=4[OH:37])[C:21]4([CH2:26][CH2:25][N:24]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:22]4)[CH2:20]3)=[O:11])[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].[OH-].[NH4+:47]>>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]3[C:36]4[C:31](=[C:32]([C:38]#[N:47])[CH:33]=[CH:34][C:35]=4[OH:37])[C:21]4([CH2:26][CH2:25][N:24]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:22]4)[CH2:20]3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)CN1CCC2(CC1)CN(c1ccccc1NC(=O)Nc1nc3ccc(Cl)cc3s1)c1c(O)ccc(C(F)(F)F)c12
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CN1CCC2(CC1)CN(c1ccccc1NC(=O)Nc1nc3ccc(Cl)cc3s1)c1c(O)ccc(C#N)c12
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To 1-(6-chlorobenzo[d]thiazol-2-yl)-3-(2-(7-hydroxy-1′-isobutyl-4-(trifluoromethyl)spiro[indoline-3,4′-piperidine]-1-yl)phenyl)urea (Example 30, 6.0 mg, 9.5 μmol) was added sodium hydroxide (95 μL, 0.095 mmol) and ammonium hydroxide (27.5 μL, 0.190 mmol). The reaction mixture was stirred at 40° C. for 18 h. The crude product was purified using a 10 minutes gradient from 0 to 100% B and pump to dryness to give the title compound Example 80 (3.5 mg, 6.0 μmol, 63% yield). 1H NMR (400 MHz, MeOD) δ ppm 1.01 (d, J=6.60 Hz, 6H), 2.12 (t, J=14.02 Hz, 3H), 2.54-2.67 (m, 1H), 2.86 (m, 1H), 2.92 (d, J=7.15 Hz, 2H), 3.01 (t, J=12.09 Hz, 1H), 3.08-3.17 (m, 1H), 3.56 (d, J=10.44 Hz, 3H), 4.20 (d, J=10.44 Hz, 1H), 6.75 (d, J=8.24 Hz, 1H), 7.03-7.14 (m, 3H), 7.16-7.26 (m, 2H), 7.30 (m, 1H), 7.59 (dd, J=8.52, 2.47 Hz, 1H), 8.10 (d, J=7.15 Hz, 1H). LCMS (ESI) m/z 587.4 (M+H)+, RT=1.69 min (Method D).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:27][O:28][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]3=[O:26].C([NH:32][OH:33])(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[NH2:9][C:8]1[C:7]2[CH:6]=[C:5]3[C:10]4([C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[N:12]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:11]4=[O:26])[CH2:27][O:28][C:4]3=[CH:3][C:2]=2[O:33][N:32]=1
Reactant: CC(=O)NO
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
To a stirred solution of 6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.40 g, 2.7 mol) and acetohydroxamic acid (0.60 g, 8.0 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (2.60 g, 8.0 mmol). The reaction mixture was stirred at ambient temperature for 18 h and water was added. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with (ethyl acetate/hexanes (2/3)+0.1% v/v 7 N methanolic ammonia) to afford 3-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.05 g, 5%): mp 190-192° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.54-8.52 (m, 1H), 7.79-7.73 (m, 1H), 7.35-7.20 (m, 5H), 7.08-6.96 (m, 3H), 6.15 (s, 2H), 5.09-4.85 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 164.2, 163.3, 158.7, 155.6, 149.9, 143.5, 137.6, 131.7, 129.4, 126.4, 124.5, 123.6, 123.1, 121.9, 116.8, 111.5, 109.9, 91.4, 81.0, 56.8, 45.3; MS (ES+) m/z 384.9 (M+1).