Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH:9]2[CH2:11][CH:3]1[CH:4]1[CH:8]2[CH2:7][CH2:6][CH2:5]1.[CH3:12][O-:13].[Na+].O>C1CCCCC1>[CH:12]([C:9]1[CH:8]=[CH:4][C:3]([CH:11]=[C:10]2[CH:9]3[CH2:11][CH:3]([CH:4]4[CH:8]3[CH2:7][CH2:6][CH2:5]4)[C:2]2=[O:1])=[CH:2][CH:10]=1)=[O:13]
Reactant: C[O-]
Reactant: O=C1CC2CC1C1CCCC21
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: O=Cc1ccc(C=C2C(=O)C3CC2C2CCCC32)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 40 mmol (6.3 g) of 8-ketotricyclo[5.2.1.02,6 ]decane and 60 mmol of sodium methoxide (11 g of a 30% solution) in 50 ml of cyclohexane are stirred at 50° C. for 30 minutes. 50 mmol (9.0 g) of terephthalaldehyde monodimethyl acetal are then added dropwise and the mixture is refluxed for 1 hour. It is then cooled to room temperature and 100 ml of water are added.
Reaction SMILES: [Br-:1].COC1C=CC(C(O)C2C=CC(OC)=CC=2)=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23](S(O)(=O)=O)=[CH:22][CH:21]=1.C[N:32]1[CH2:36]CCC1=O>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:30]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:32][CH:36]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN1CCCC1=O
Agent: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Brc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of the above bromide (1.09 g, 2.8 mmol) was added 4,4′-dimethoxybenzhydrol (818 mg, 3.4 mmol) and p-toluenesulfonic acid (532 mg, 2.8 mmol) in benzene (60 mL) and N-methylpyrrolidinone (6 mL) were heated to reflux. After 24 h the reaction was allowed to cool to room temperature and diluted with ethyl acetate (200 mL). The organic layer was washed with NaHCO3 (2×), H2O (2×), and Brine(2×), dried over anhydrous MgSO4, filtered and the solvent removed in vacuo. The crude material was purified via column chromatography (10% EtOAc-Hexane) to provide the desired DMB protected 3-bromoindole derivative (1.5 g, 2.4 mmol, 87% yield) as an orange solid: (ESII-MS (M+H) 616.5 m/e).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[C:8]([OH:10])=O.[CH3:12][NH:13][C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]CCC)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[CH3:12][N:13]([C:8](=[O:10])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:11])[C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: CC(C(=O)O)c1ccccn1
Product: CC(C(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1)c1ccccn1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 2-(pyridin-2-yl)propanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 392.
Reaction SMILES: CC(NCC(O)COC1C=CC=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)C.CC1[N:29]([C:30]([C:32]2[CH:33]=CC(Cl)=C[CH:37]=2)=[O:31])[C:28]2[CH:27]=[CH:26][C:25](OC)=[CH:24]C=2C=1CC(O)=O.C[N:46](CCN(C1C=CC=CN=1)CC1C=CC(OC)=CC=1)C>>[CH3:33][C:32]1[C:30](=[O:31])[N:29]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:28]2[C:27]([CH:37]=1)=[CH:26][CH:25]=[CH:24][N:46]=2
Reactant: COc1ccc(CN(CCN(C)C)c2ccccn2)cc1
Reactant: CC(C)NCC(O)COc1cccc2ccccc12
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Product: Cc1cc2cccnc2n(-c2ccccc2)c1=O
Reaction time: 2 h

Procedure:
The sensitized guinea pigs are injected i.v. with 1 mg/kg propranolol, 5 mg/kg indomethacin and 2 mg/kg mepyramine given together in a volume of 1 ml/kg. Fifteen minutes later the animals are challenged with nebulized ovalbumin. Test compounds are administered orally 2 hours before challenge with ovalbumin. Suppression of anaphylactic bronchospasm is expressed as a percent inhibition of the peak increase in intratracheal pressure by comparison to a vehicle-treated control group. In this procedure, 3-methyl-1-phenyl-1,8-naphthyridin-2(1H)-one (referred to as Compound A hereinafter) provided a 96% inhibition at a dose of 5 mg/kg p.o.
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.CN(C)CCNC1N=[N+:23]([O-:36])[C:24]2[CH:30]=[C:29]3CC[CH2:33][CH2:34][CH2:35][C:28]3=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=[O:39]>C(Cl)Cl.N>[N+:23]([C:24]1[CH:30]=[C:29]2[C:28]([CH2:35][CH2:34][CH2:33]2)=[CH:27][C:25]=1[NH:26][C:10](=[O:11])[CH3:12])([O-:36])=[O:39]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCCCC3
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.31 mL, ca. 6.2 mmol) was added dropwise to a stirred solution of TFAA (0.9 mL, 6.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 188 (186 mg, 0.6 mmol) and TFA (0.24 mL, 3.1 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 188 (43 mg, 23%) and (ii) 1,4-dioxide 189 (82 mg, 42%) as a red solid: mp (MeOH) 131-133° C.; 1H NMR δ 8.03 (s, 1H, H-11), 7.99 (s, 1H, H-5), 7.36 (br s, 1H, NH), 3.63 (br t, J=6.0 Hz, 2H, CH2N), 2.98-3.03 (m, 2H, CH2), 2.91-2.95 (m, 2H, CH2), 2.60 (br t, J=6.0 Hz, 2H, CH2N), 2.30 [s, 6H, N(CH3)2], 1.82-1.89 (m, 2H, H-8), 1.68-1.76 (m, 4H, H-7, H-9); 13C NMR δ 154.4, 149.7, 144.7, 137.1, 128.7, 119.8, 115.9, 57.5, 45.2 (2), 38.9, 37.0, 36.2, 31.8, 28.4, 28.2. Anal. calcd for C16H23N5O2.¼CH3OH: C, 60.0; H, 7.4; N, 21.5. Found: C, 59.9; H, 7.0; N, 21.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15](=O)[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3C2=O)=[C:4](C(=O)C2C=CC=CC=2)[CH:3]=1>C(O)C.[OH-].[Na+].Cl.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:8][CH2:9][CH2:10][N:11]=[C:15]([C:14]3[CH:13]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCCC2

Procedure:
A solution of 5.1 g (12.6 mmole) of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropane in 100 ml of ethanol and 20 ml of 3N sodium hydroxide was refluxed for 2 hr. The solution was diluted with 60 ml of 3N hydrochloric acid and refluxed for 12 hr. The mixture was diluted with water and extracted with ether. The aqueous layer was separated, made alkaline with dilute sodium hydroxide, and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was purified by plug filtration (silica gel, 10 g; eluent, methylene chloride) and the eluent was acidified with methanolic hydrogen chloride. The solution was concentrated at reduced pressure to dryness and the residue was crystallized from a mixture of isopropanol and ether to give a colorless solid, mp 234°-235° C. Recrystallization from a mixture of methylene chloride and ether gave colorless needles, mp 234°-235° C. dec.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][OH:13].[C-]#N.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[OH:13][NH:12][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COC(=O)Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccccc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To methyl phenylacetate (0.288 mL, 2.0 mmol) in THF:MeOH: 50% aqueous NH2OH (1:1:0.5, 2.5 mL) was added KCN (5 mg, 0.08 mmol, 4 mol %) and the mixture was stirred at ambient temperature. After 2 h the reaction was complete by HPLC. To the mixture was added saturated aqueous citric acid (25 mL) followed by extraction with EtOAc (3×25 mL). The organic phase was isolated, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase HPLC (C-18, 5μ 100×30 mm column), eluting with a gradient of acetonitrile: water (0.05% TFA). Following lyophilization of the product fractions there was obtained pure N-hydroxy-2-phenylacetamide as a fluffy solid (0.234 g, 77% yield): LRMS (M+H)+: 152.1 m/z; 1H NMR (DMSO-d6) δ: 10.6(s, 1H), 8.81(s, 1H), 7.2(m, 5H), 3.26(s, 2H); Anal (C,H,N): % C: (calc) 63.56; (found) 63.63; % H: (calc.) 6.00; (found) 5.91; % N: (calc.) 9.27, (found) 9.04.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14].CON(C)[C:25](=O)[C@H:26]([CH2:28][CH2:29][CH2:30][CH3:31])[NH2:27]>C(Cl)Cl>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]1[CH:25]=[C:26]([CH2:28][CH2:29][CH2:30][CH3:31])[NH:27][C:1]1=[O:2])[CH3:14]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCc1ccccc1N
Reactant: CCCC[C@H](N)C(=O)N(C)OC
Solvent: ClCCl
Product: CCCCc1cn(-c2ccccc2CC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.4 %

Procedure:
Under nitrogen, a solution of 4.86 g (30 mmol) of carbonyl diimidazole in 50 mL of methylene chloride was treated with 3.63 g (30 mmol) of 2-ethylaniline (Aldrich). The reaction was allowed to stir at ambient temperature for 90 min prior to the addition of 4.80 g (30 mmol) of L-norleucine-N-methoxy-N-methylamide from Step 3. The reaction was stirred overnight, filtered and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethylacetate/hexane (40:60) gave 2.45 g (25%) of the 2-ethylphenyl urea of L-norleucine-N-methoxy-N-methylamide as a colorless solid: NMR (CDCl3) δ0.88 (t, J=7 Hz, 3H), 1.14 (t, J=8 Hz, 3H), 1.30-1.38 (m, 2H), 1.38-1.60 (m, 2H), 1.63-1.80 (m, 2H), 2.49 (t, J=7 Hz, 2H), 2.56 (t, J=8 Hz, 2H), 3.20 (s, 3H), 3.82 (s, 3H), 4.18-4.27 (m, 1H), 4.96 (5, J=8 Hz, 1H), 6.77 (br s, 1H), 7.05-7.22 (m, 2H), 7.32-7.43 (m, 1H), 7.54 (d, J=8 Hz, 1H). A solution of 2.37 g (7.4 mmol) of this urea in 50 mL of anhydrous THF/ether (1:1) was treated with 9.2 mL (9.2 mmol) of 1M LAH in ether at ambient temperature. The reaction was allowed to stir for 90 min and was slowly treated with a solution of 1.77 g (13 mmol) of KHSO4 in 45 mL of water. This mixture was rapidly stirred for 3 hr and then the layers were separated. The aqueous layer was extracted three times with ether and the extracts were combined with the organic layer. The etheral solution was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was dissolved in 30 mL of methylene chloride, treated with 0.5 mL of TFA, and stirred at reflux for 3 hr. The reaction was cooled to ambient temperature, washed with NaHCO3 (sat), dried (MgSO4), and concentrated in vacuo to give 1.8 g (100%) of 1-(2-ethylphenyl)-4-butyl-1,3-dihydro-2H-imidazol-2-one as a colorless oil: NMR (CDCl3) δ0.92 (t, J=7 Hz, 3H), 1.17 (t, J=7, Hz, 3H), 1.38 (m, J=7 Hz, 2H), 1.58 (m, J=7 Hz, 2H), 2.46 (t, J=7 Hz, 2H), 2.58 (q, J=7 Hz, 2H), 6.06 (s, 1H), 7.16-7.30 (m, 2H), 7.30-7.40 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](O)=[O:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[S:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:20])[NH:30][C:29]3[CH:31]=[CH:32][C:26]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:27][CH:28]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Product: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Yield: 59.1 %

Procedure:
A procedure similar to that described in Example 52 was carried out with trans-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (50 mg, 0.14 mmol) and p-sulfamoylaniline (25 mg, 0.15 mmol) to give 42 mg of the title compound (58%) after recrystallization from acetone-methanol-water: mp 279.5°~295° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.09 (s, 1H), 10.32 (s, 1H), 7.76 (d, 2H, J=8.9 Hz), 7.70 (d, 2H, J=8.9 Hz), 7.23 (s, 2H), 7.21 (s, 1H), 7.18 (s, 1H), 4.95~5.05 (m, 1H), 3.21 (dd, 1H, J=17.8, 5.9 Hz), 2.52~2.66 (m, 3H), 2.28~2.42 (m, 1H), 0.87 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:12]=[O:13])=[N:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH2:14](O)[CH2:15][OH:16].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1
Reactant: OCCO
Reactant: COc1ccc([N+](=O)[O-])nc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc([N+](=O)[O-])nc1C1OCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 884.2 %

Procedure:
A mixture of 0.55 g (0.3 mmol) 3-methoxy-6-nitro-pyridine-2-carbaldehyde, 0.8 ml (15 mmol) of ethylene glycol, and 10 mg (catalytic amount) of p-toluene sulfonic acid was refluxed in 50 ml of toluene using a Dean-Stark trap to trap water. After 90 minutes, the reaction mixture was cooled to room temperature and the solvent evaporated. The residue was chromatographed on silica using 5:1 (chloroform/ethyl acetate) as the elutant. Appropriate fractions were combined and evaporated to yield 0.6 g of 2-[1,3]dioxolan-2-yl-3-methoxy-6-nitro-pyridine as an oil. TLC: Rf=0.9 (1:1 chloroform/ethyl acetate). 1H NMR (CDCl3) δ 8.25 (d, 1H), 7.40 (d, 1H), 6.30 (s, 1H), 4.30 (m, 2H), 4.10 (m, 2H), 4.0 (s, 3H). Mass Spectrum: m/e=227.2 (p+1).
Reaction SMILES: C(O)C.Cl.[NH2:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[C:8]2[CH:14]=[C:13]([Cl:15])[S:12][C:9]2=[N:10][CH:11]=1.O1CCCC1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]=[C:37]=[O:38]>C(N(CC)CC)C>[Cl:15][C:13]1[S:12][C:9]2=[N:10][CH:11]=[C:6]([NH:5][C:37]([NH:36][C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])=[O:38])[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[C:8]2[CH:14]=1
Reactant: Cc1ccccc1-c1c(N)cnc2sc(Cl)cc12
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1c(NC(=O)Nc2ccc(F)cc2F)cnc2sc(Cl)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
To a mixture of 5-amino-2-chloro-4-(2-methylphenyl)thieno[2,3-b]pyridine hydrochloride ethanol solvate (160 mg) and tetrahydrofuran (3 ml) were added dropwise triethylamine (0.07 ml) and 2,4-difluorophenyl isocyanate (0.12 ml). The mixture was stirred at room temperature for 5 hours and the solvent was distilled off. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over MgSO4 and the solvent was distilled off. To the residue was added isopropyl ether to obtain N-[2-chloro-4-(2-methylphenyl)thieno[2,3-b]pyridin-5-yl]-N'-[2,4-difluorophenyl)urea (133 mg, 68.9%) as crystals. The crystals were recrystallized from ethanol to obtain colorless prisms, mp; 225°-226° C.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(CC)CC.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[F:36][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([CH:29]6[CH2:34][CH2:33][N:32]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:31][CH2:30]6)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C3CCNCC3)ccn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C3CCN(S(C)(=O)=O)CC3)ccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-(piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (92) (15.6 mg, 0.032 mmol) and Et3N (0.013 mL, 0.095 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (0.0074 mL, 0.095 mmol) and stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (F49). MS (m/z) 571.1 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][CH:12]([O:11][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)[C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(Cl)Oc1ccc(-c2ccccc2)cc1

Procedure:
1,292 g (4.83 moles) of 1-(4'-phenyl-phenoxy)-3,3-dimethylbutan-2-one were dissolved in 2.5 l of methylene chloride and 400 ml (4.9 moles) of sulfuryl chloride were added dropwise at the boil. The mixture was heated under reflux for 15 hours and was then concentrated by distilling off the solvent. After adding 250 ml of carbon tetrachloride, the solvent was again distilled off under a water-pump vacuum (bath temperature 65° C.). Crude 1-chloro-1-(4'-phenyl-phenoxy)-3,3-dimethylbutan-2-one was obtained quantitatively, and was used further in the form obtained. ##STR3##
Reaction SMILES: CC(C)=O.[CH3:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+:16]([O-])=O)[C:7]=1[NH:19][C:20](=[O:26])[C:21](OCC)=[O:22]>Cl.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[F:13][C:12]([F:15])([F:14])[C:10]1[CH:9]=[C:8]2[C:7]([NH:19][C:20](=[O:26])[C:21](=[O:22])[NH:16]2)=[C:6]([CH3:5])[CH:11]=1
Reactant: CCOC(=O)C(=O)Nc1c(C)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
355 ml of a 15% titanium trichloride solution in aqueous hydrochloric acid are dissolved in 850 ml of water and 850 ml of acetone under a nitrogen atmosphere at 0° C. A solution of 35.5 g (110.8 mmol) of ethyl N-(2-methyl-6-nitro-4-trifluoromethylphenyl)oxamate in 1.7 1 of acetone is slowly added dropwise. The resulting violet solution is stirred at 0° C. for 16 hours. 15% titanium trichloride solution in aqueous hydrochloric acid is then added until, according to 1H-NMR analysis, starting material is no longer detectable. The reaction mixture is filtered off on a suction filter, the filtrate is concentrated and the deposited solid is filtered off again on a suction filter. The crude product is washed with dilute hydrochloric acid and water. The title compound is obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]2[CH:7]=[C:8]([CH:11](O)[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCl>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][C:2]([CH3:1])([CH3:16])[C:6]=2[CH:7]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(O)c1ccc2c(c1)C(C)(C)CO2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1ccc2c(c1)C(C)(C)CO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
To a cold solution (0° C.) of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-ol (1.97 g, 8.93 mmol) in dry dichloromethane (40 mL) was added triethylsilane (2.85 mL, 17.86 mmol). After 10 minutes, trifluoroacetic acid was the reaction mixture stirred at 0° C. for 30 minutes. Water was poured into the reaction mixture and the layers separated. The organic layer was further washed with water, aqueous NaHCO3 and brine, dried (Mg2SO4), filtered and evaporated. The residue was purified on silica gel (0% to 5% ethyl acetate in hexane) to give 1.6 g of 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (87%). 1H NMR (300 MHz; CDCl3): δ 0.90 (d, J=6.3 Hz, 6 H), 1.32 (s, 6 H), 1.79 (m, 1 H), 2.40 (d, J=6.9 Hz, 2 H), 4.20 (s, 2 H), 6.68 (dd, J=1.2 Hz and 7.5 Hz, 1 H), 6.87 (m, 2 H).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(C(C2[C:22]([CH2:23][O:24][CH2:25][C:26]3[C:31](C4C(=CC=C(O)C=4)O)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)=CC(=CC=1)O)O.[OH-:40].[K+]>CS(C)=O>[CH2:25]([O:24][C:23]1[CH:18]=[CH:19][C:20]([O:40][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:21][CH:22]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 197.7 %

Procedure:
Ethyl 2-bromopropionate (36.2 g) and hydroquinone monobenzyl ether (40.0 g) were dissolved in dry dimethyl sulfoxide (100 ml), and pulverized potassium hydroxide (11.2 g) was added to the resultant solution. After stirring at room temperature for 20 hours, the reaction mixture was poured into ice-water (500 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with 1N hydrochloric acid, water, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the residue obtained by evaporation of the solvent under a reduced pressure was purified by medium pressure column chromatography using silica gel, to obtain ethyl 2-(4-benzyloxyphenoxy)propionate (57.3 g).
Reaction SMILES: C(SCC)C.[Al+3].[Cl-].[Cl-].[Cl-].C[O:11][C:12]1[C:13]([CH3:33])=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1>C(Cl)Cl>[OH:11][C:12]1[C:13]([CH3:33])=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1Cc2cc(C)c(OC)cc2Cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCSCC
Product: CCOC(=O)CC1Cc2cc(C)c(O)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
To dry CH2Cl2 (30 mL) cooled in an ice bath was added diethylsulfide (0.38 mL, 3.3 mmol) followed by AlCl3 (438 mg, 3.3 mmol). To this solution was added dropwise a solution of ethyl (±)-10,11-dihydro-3-methoxy-2-methyl-5H-dibenzo[a,d]cycloheptene-10-acetate (200 mg, 0.6 mmole) in dry CH2Cl2 (6 mL), and the resulting mixture was stirred at RT for 2 hr. The reaction was quenched with 1.0 N HCl (10 mL), and the layers were separated. The organic layer was dried (MgSO4) and concentrated on the rotavap to give the title compound (100 mg, 56%) as a colorless oil: MS (ES) m/e 311.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[C-:17].[CH:23](=O)[CH3:24]>Cl(O)(=O)(=O)=O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][NH:16][C:17]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]2=[N:1][C:23]=1[CH3:24]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC=O
Reactant: Nc1ncccc1OCc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CNc1c(C)nc2c(OCc3ccccc3)cccn12

Procedure:
Compound (31) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3-benzyloxypyridine solution (0.1 M, DCM), 0.575 ml of methyl isocyanoacetate solution (0.2 M, DCM), 0.500 ml of acetaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).