Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[NH:16][C:15]1=[O:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>CC#N.C1COCC1>[CH:1]([N:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:17](=[O:26])[N:16]([CH3:29])[C:15]1=[O:27])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Reactant: CI
Solvent: C1CCOC1
Solvent: CC#N
Product: Cn1c(=O)c(-c2ccccc2)cn(C(c2ccccc2)c2ccccc2)c1=O
Yield: 43 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 16 (Step 1) starting from 1-benzhydryl-5-phenyl-pyrimidine-2,4-dione (prepared as in Example 14, Step 2) (0.37 g, 1.01 mmol); a 1:1 mixture of was dry MeCN/THF and iodomethane were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 80:20) to afford the title compound (0.16 g, 43%) as a light-red solid. 1H NMR (400 MHz, CDCl3): δ 3.46 (s, 3H), 7.19-7.24 (m, 6H), 7.28-7.43 (m, 11H). MS (ESI) m/z: 369 [m-H]+.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>C(N(CC)CC)C.C(#N)C.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)I>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)Oc1ccc(I)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OC(F)F)cc1
Yield: 95.7 %

Procedure:
A solution of 1-(difluoromethoxy)-4-iodobenzene (12.7 g, 50 mmol) in triethylamine (175 mL) was treated with tetrakis(triphenylphosphine)palladium (4.0 g, 3.5 mmol), copper iodide (925 mg, 4.85 mmol), and a solution of ethynyl(trimethyl)silane (6.9 mL, 50 mmol) in acetonitrile at room temperature, stirred for 1 h at 60° C. and concentrated in vacuo. The resultant residue was dissolved in Et2O, filtered and the filtrated was concentrated in vacuo. This residue was purified by chromatography (silica gel, EtOAc/hexane:5/95) to give {[4-(difluoromethoxy)-phenyl]ethynyl}(trimethyl)silane (11.5 g, 96%) as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]Cl)[CH2:2][CH2:3][CH3:4].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Yield: 86.6 %

Procedure:
A solution of 4-butoxy-6-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.59 g, 4.5 mmol) and potassium phthalimide (1.26 g, 6.8 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-{(4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (1.81 g, 86.6%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[N:19]([CH3:27])[CH:18]=1.[C:33]([O-:36])([O-])=O.[K+].[K+]>>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:2][C@H:3]2[CH2:33][O:36][CH2:6][CH2:5][O:4]2)[S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[N:19]([CH3:27])[CH:18]=1
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(NS(=O)(=O)CC)ccc1Oc1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc(=O)n(C)cc1-c1cc(N(C[C@H]2COCCO2)S(=O)(=O)CC)ccc1Oc1ccc(F)cc1F
Yield: 75.5 %

Procedure:
A stock solution of Example 72A (0.16 M in DMF, 200 μL, 0.03 mmol Example 72A (1.0 equivalent)), K2CO3 (13.4 mg, 0.096 mmol, 3.2 equivalents) and (25)-4-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (0.04 M in DMA, 89 μL, 0.036 mmol, 1.2 equivalents), were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6 5 min linear gradient 5-60% A, 6.5-7.0 min linear gradient 60-100% A, 7.0-8.9 min 100% A, 8.9-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to yield the title compound (6.39 mg, 32% yield). 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.56 (m, 1H), 7.44-7.38 (m, 2H), 7.29 (m, 1H), 7.15-7.03 (m, 2H), 6.96 (m, 1H), 5.87 (s, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.80 (m, 1H),3.77-3.72 (m, 2H), 3.70-3.62 (m, 2H), 3.61-3.49 (m, 4H), 3.44 (s, 3H), 3.20 (m, 2H), 1.31 (t, J=7.4 Hz, 3H), 1.24 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 565.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li:15])CCC>CCOCC>[CH3:1][C:2]1[CH:10]([Li:15])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCOCC
Product: [Li]C1C(C)=Cc2ccccc21
Reaction time: 2.5 h
Yield: 85 %

Procedure:
2-methylindene (47.2 g) was dissolved in ether (400 ml) and n-butyl lithium (145.2 ml, 2.5M in Hexane) was added dropwise over 3 hours. The mixture was stirred for 2.5 hours. After evaporation of the solvent, the residual solid was washed twice with n-pentane (400 ml). Drying under vacuum gave 2-methylindenyl lithium (42 g, 85%) as a pale brown powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: COCc1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: COCc1ccc(NN)nc1

Procedure:
2.2 g (14.0 mmol) of the compound from Example 12A are initially charged in 10 ml of ethanol. 7.0 g (140.0 mmol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The reaction mixture is then reacted again in a single-mode microwave oven (CEM Explorer) at 150° C. for 2 h. The mixture is then concentrated on a rotary evaporator, taken up in ethyl acetate, washed once with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated again, and the residue is dried under high vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1.Cl>ClCCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccccc1N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(RK1-1-22) I A solution of 4-nitrobenzenesulfonyl chloride (200 mg, 0.90 mmol), o-toluidine (106 mg, 0.99 mmol), and pyridine (79 mg, 0.08 ml, 0.993 mmol) in 5.0 mL 1,2-dichloroethane was heated to 150° C. for 10 minutes in the microwave. A 1M HCl solution was added until the pH of the mixture indicated pH=2, and the acidified aqueous layer was separated and extracted with CH2Cl2 (3×10 mL). The combined organic fractions were washed successively with brine and water then dried over Na2SO4 and evaporated to dryness to afford the title compound as a peach solid (127 mg, 47%). Mp=139-142° C. (lit. 157-159° C., Tetrahedron 62(25), 6100-6106; 2006); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=9.0 Hz, 2H), 7.89 (d, J=9.0 Hz, 2H), 7.28-7.27 (m, 1H), 7.20-7.12 (m, 3H), 6.30 (br s, 1H), 2.01 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Cc1ccccc1Br
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1ccccc1N1CCOCC1
Yield: 39.5 %

Procedure:
According to the general procedure B, 2-bromotoluene (171 mg, 1.00 mmol) reacted with morpholine (104 mg, 1.20 mmol) using 1 mol % of catalyst and sodium tert-butoxide (134 mg, 1.40 mmol) at room temperature for 43 h to give the title compound (70 mg, 40%) as an oil after purification: 1H-NMR (300 MHz, CDCl3): δ 7.22-7.18 (m, 2H), 7.06-7.00 (m, 2H), 3.87 (t, 4H, J=4.5 Hz), 2.93 (t, 4H, J=4.5 Hz), 2.34 (s, 3H). GC/MS(EI): m/z 177 (M+).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH3:21].Cl>C(O)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=3[Cl:3])[C:11]=2[CH:12]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Yield: 90.7 %

Procedure:
Ethanol (80 li) and 10% sodium hydroxide aqueous solution (37 g) are added to 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (10.0 g), and the solution is refluxed for 4 hours. After the reaction solution is cooled, its acidity is adjusted to pH 6 with 10% hydrochloric acid. The sediment is gathered, washed with water, dried under reduced pressure, and thus, 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (8.30 g) is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][C:31]([OH:33])=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.O[N:35]1[C:39]2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.O1CCCC1>CN(C)C=O>[CH3:39][NH:35][C:31](=[O:33])[CH2:30][CH:27]1[CH2:28][CH2:29][CH:24]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9]2)[CH2:25][CH2:26]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CC(=O)O)CC1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)CC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 60 °C
Yield: 26.2 %

Procedure:
A mixture of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetic acid (0.094 g, 0.21 mmol), 1-hydroxy-7-azabenzotriazole (0.044 g, 0.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.082 g, 0.43 mmol), 2M methylamine in tetrahydrofuran (2.13 mL, 4.26 mmol) and N,N-dimethylformamide (1.50 mL) was heated at 60° C. overnight. The mixture was allowed to cool to ambient temperature and purified by preparative RP-HPLC to yield N1-methyl-2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetamide (0.025 g, 0.055 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.24(s, 1H), 7.42(d, 2H), 7.38 (t, 2H), 7.16(t, 1H), 7.07(m, 5H), 5.82(br, 2H), 5.62(br, 1H), 4.70(m, 1H), 2.83 (d, 3H), 2.36-1.70(m, 11H); MS: MH+ 456; TLC (ethyl acetate) Rf 0.34; RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.32 min.
Reaction SMILES: [CH2:1]1[CH:8]([NH2:9])[C:6](=[O:7])[NH:5][C:3](=[O:4])[CH2:2]1.Cl.Br[CH2:12][C:13]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15](OC)=[O:16].C(N(CC)CC)C>CN(C)C=O>[O:16]=[C:15]1[C:14]2[C:13](=[C:22]([CH3:23])[CH:21]=[CH:20][CH:19]=2)[CH2:12][N:9]1[CH:8]1[CH2:1][CH2:2][C:3](=[O:4])[NH:5][C:6]1=[O:7]
Reactant: NC1CCC(=O)NC1=O
Reactant: COC(=O)c1cccc(C)c1CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 16.25 g of 2,6-dioxopiperidin-3-ammonium chloride, and 30.1 g of methyl 2-bromomethyl-3-methylbenzoate, and 12.5 g of triethylamine in 100 mL of dimethylformamide is stirred at room temperature for 15 hours. The mixture is then concentrated in vacuo and the residue mixed with methylene chloride and water. The aqueous layer is separated and back-extracted with methylene chloride. The combined methylene chloride solutions are dried over magnesium sulfate and concentrated in vacuo to give 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>N1C=CC=CC=1.O1CCCC1>[CH3:26][O:25][C:21]1[CH:20]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:22]=1[O:23][CH3:24])[C:17]([NH:11][C:5]1[C:6](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8])=[O:18]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(C(=O)Nc2ccc(Cl)cc2C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of 1.7 g of 5-chloroanthranilic acid in 40 ml of pyridine is added a solution of 2.6 g of 3,4,5-trimethoxybenzoylchloride in tetrahydrofuran under cooling, and the mixture is stirred at room temperature for 2 hours and then heated to 80° C. for 30 minutes. The reaction mixture is concentrated under a reduced pressure and to the residue is added water. The precipitated crystals are recrystallized from acetone to obtain 1.4 g of N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilic acid as colorless needles.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)cc2)cc1O

Procedure:
The title compound was prepared from 4′-(2-Benzyl-benzo[b]thiophen-3-yl)-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 236-238° C.; MS m/e 591 (M-H)+;
Reaction SMILES: Cl[C:2]1C=C(C=C(C)N=1)C(O)=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[N:23]=1)[C:18]([OH:20])=[O:19])[CH3:13]>C(O)(C)C>[CH:12]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[N:23]=1)[C:18]([OH:20])=[O:19])([CH3:2])[CH3:13]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: CCOc1cc(C(=O)O)cc(C)n1
Solvent: CC(C)O
Product: Cc1cc(C(=O)O)cc(OC(C)C)n1

Procedure:
2-Isopropoxy-6-methyl-isonicotinic acid is prepared starting from 2-chloro-6-methyl-isonicotinic acid in analogy to 2-ethoxy-6-methyl-isonicotinic acid using isopropanol as solvent; LC-MS: tR=0.70 min, [M+1]+=196.04.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:25]1[C:30]([Cl:31])=[N:29][C:28]([Cl:32])=[CH:27][C:26]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[Cl:32][C:28]1[CH:27]=[C:26]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:25]=[C:30]([Cl:31])[N:29]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)nc(Cl)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2,6-dichloropyridin-4-isocyanate (230 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 287 mg (81.1%) of the desired product as a solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[C:15]2[C:14](=[O:16])[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]=2[NH:9][CH:8]=1.CN([CH:22]=[O:23])C>>[CH3:6][C:7]1[C:15]2[C:14](=[O:16])[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1[CH:22]=[O:23]
Reactant: Cc1c[nH]c2c1C(=O)C(C)(C)CC2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)C(C)(C)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
POCl3 1.2 mL (13.1 mmol) was added dropwise into anhydrous DMF 15 mL with cooling on ice bath. After 10 minutes, a solution of 3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole 1.500 g (8.463 mmol) in anh. DMF was added dropwise over a 10 min period. The cooling bath was allowed to expire and the reaction was stirred at ambient temperature overnight (11 hours). With cooling on ice bath, the reaction mixture was quenched by addition of crushed ice and ice-cold water (approx 150 mL total). The reaction mixture was then alkalized to pH=10 (approximately, on pH paper strip) by gradual addition of potassium carbonate solution, the total volume was adjusted to about 250 mL with additional water and the mixture was stirred at ambient temperature for 1 day. The resulting slurry was cooled on ice bath, the precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac. Y=1.351 g (77.5%) of a white microcrystalline solid. 1H-NMR (d6-DMSO, 400 MHz): 12.14 (br s, 1H), 89.66 (s, 1H), 2.79 (t, 6.1 Hz, 2H), 2.48 (s, 3H), 1.86 (t, 6.3 Hz, 2H), 1.06 (s, 6H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][N:34]([CH3:42])[CH:35]([CH3:41])[CH2:36][CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C.CN(C=O)C>CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:33][N:34]([CH3:42])[CH:35]([CH3:41])[CH2:36][CH2:37][C:38]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:39]
Reactant: CC(CCC(=O)O)N(C)C
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(CCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1,150 mg, 0.342 mmol), 4-(dimethylamino)pentanoic acid (63.6 mg, 0.514 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (131.5 mg, 0.69 mmol), and 4-dimethylaminopyridine (10.5 mg, 0.09 mmol) were added to DMF (3 ml). The reaction was allowed to stir overnight at room temperature followed by addition to EtOAc (40 ml). The precipitate was collected by filtration and then purified by column chromatography 0–5% MeOH/CH2Cl2 to yield a white powder (100 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([O:14][C:15](Cl)=[O:16])[CH:11]=[CH:12][CH:13]=1)=[O:6])[C:2]#[CH:3].[CH2:18]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C.O>[CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([O:14][C:15](=[O:16])[N:22]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6])[C:2]#[CH:3]
Reactant: C#CCOC(=O)Nc1cccc(OC(=O)Cl)c1
Reactant: Cc1ccc(NCC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOC(=O)Nc1cccc(OC(=O)N(CC(C)C)c2ccc(C)cc2)c1
Temperature: 15 °C

Procedure:
A solution of 25.4 g (0.1 mol) of chloroformic acid-3-(2-propinyl-oxycarbonylamino)-phenylester in 100 ml acetic acid ethylester is added within a period of 20 minutes to a solution of 16.3 g (0.1 mol) of N-isobutyl-p-toluidine in 50 ml acetic acid ethylester. Simultaneously a solution of 13.8 g (0.1 mol) of potassium carbonate in 50 ml water is added dropwise while stirring and cooling to 15° C. temperature. Thereafter, the solution is further stirred at 15° C. for 30 minutes. The organic phase is then separated and washed at 0° C. with dilute sodium hydroxide, dilute hydrochloric acid and water. After drying on magnesium sulfate the mass is concentrated at a reduced pressure. It is then recrystallized from acetic acid ethylester/pentane.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1O>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][C:30]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2cc(C(F)(F)F)ccc2F)CC1
Yield: 35 %

Procedure:
Prepared in analogy to Example 4 from (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) and 2-fluoro-5-(trifluoromethyl)phenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 35%). MS (m/e): 504.4 (M+H+, 100%).