Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:20]([C:22]1[NH:26][C:25]([CH3:27])=[C:24]([C:28]([OH:30])=O)[C:23]=1[CH3:31])=[O:21].ON1C2C=CC=CC=2N=N1.[CH3:42][N:43]([CH3:51])[C:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=1>O.CN(C=O)C>[CH3:42][N:43]([CH3:51])[C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:28]([C:24]2[C:23]([CH3:31])=[C:22]([CH:20]=[O:21])[NH:26][C:25]=2[CH3:27])=[O:30])=[CH:46][CH:45]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CN(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=O)c(C)c1C(=O)Nc1ccc(N(C)C)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.074 g, 5.6 mmol), triethylamine (1.12 mL, 8 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (0.668 g, 4 mmol) and 1-hydroxybenzotriazole (0.756 g, 5.6 mmol) were added to DMF (10 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then N,N-dimethyl-p-phenylenediamine (1.09 g, 8 mmol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 1.2 mL of water and 1 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (25 mL×3), the combined organic phase was washed with saturated salt water (30 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed (silica gel column chromatography, eluent: methanol:ethyl acetate=1:2) to give 0.682 g (2.4 mmol) of N-[4-(dimethylamino) phenyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide. Yield 59.9%. 1HNMR (DMSO-d6) δ 10.92 (s, br, 1H, NH), 9.64 (s, 9.34 (s, br, 1H, NH), 7.54-7.52 (d, 2H), 6.77-6.74 (d, 2H), 3.38-2.58 (s, 6H), 2.58-2.56 (m, 3H), 2.55-2.41), (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][C@H:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:12]=[CH:11]/[CH2:10][C@@H:9]([OH:13])[CH3:8])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C=CC[C@H](C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](O)C/C=C/c1cccnc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 3-bromopyridine (11.22 g, 70.58 mmol), (2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (527 mg, 2.35 mmol), tri-o-tolylphosphine (1.79 g, 5.88 mmol), triethylamine (30 mL, 216 mmol) and acetonitrile (30 mL) were heated in a sealed glass tube at 130–140° C. for 8 h. The reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure on a rotary evaporator. Water (20 mL) was added and the mixture was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation, producing a pale-yellow oil (6.00 g). The crude product was purified by column chromatography over silica gel, eluting with chloroform-acetone (95:5, v/v). Selected fractions were combined and concentrated by rotary evaporation, affording 3.95 g (41.7%) of a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.Cl.C([N:19]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:19])=[O:15]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(O)c(C(N)=O)cnc2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 114.9 %

Procedure:
A solution of 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid (3.06 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.17 g), and N-hydroxybenzotriazole (2.53 g) in N,N-dimethylformamide (45 ml) was stirred at 0° C. for 15 minutes. (2E,4E)- and (2Z,4E)-4-Methyl-2,4-heptadien-1-ylamine (2.35 g) was added to the solution. The solution was stirred at 0° C. for 2 hours and then at room temperature overnight. The reaction mixture was diluted with water. The resulting precipitate was filtered and washed with water to give N-[(2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-yl]-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxamide (3.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:23])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:23])=[C:13]2[C:17]=1[N:16]([CH3:26])[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccccc3)c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccccc3)c2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 18 a) except for using 8.00 g (24.3 mmol) of ethyl 7-benzyloxy-4-chloro-2-indolecarboxylate, 0.97 g (24.3 mmol) of 60% sodium hydride, 10.3 g (72.8 mmol) of methyl iodide and 200 ml of dimethylformamide. Ethyl 7-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate was thus obtained in the yield of 7.71 g (92.4%).
Reaction SMILES: [C:1]([C:9]1[C:21]([O:22]C)=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[C:11]([CH2:24][CH:25]=[CH2:26])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.[Cl-].[NH4+]>ClCCl>[C:1]([C:9]1[C:21]([OH:22])=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[C:11]([CH2:24][CH:25]=[CH2:26])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCc1cc(C(=O)c2ccccc2)c(OC)cc1OCCCCC#N
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCc1cc(C(=O)c2ccccc2)c(O)cc1OCCCCC#N
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A mixture of 0.22 g of 5-(4-benzoyl-5-methoxy-2-allylphenoxy)pentanenitrile, 2.52 ml of a 1M solution of boron tribromide in dichloromethane, and 50 ml of methylene chloride were stirred at -78° C. for two hours. The solution was poured into a cold saturated ammonium chloride solution and ice. The mixture was extracted with ethyl acetate, the organic layer was washed with a cold saturated ammonium chloride solution followed by a saturated sodium chloride solution, dried and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1:1 ethyl acetate/hexane providing 50 mg of the desired title product, m.p.=60°-62° C. NMR, MS.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([OH:16])[CH:9]=1.Cl>CCO>[OH:16][C:10]1[CH:9]=[C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: Brc1nccs1
Reactant: N#Cc1ccc(N)cc1O
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(Nc2nccs2)cc1O
Temperature: 90 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.94 mL, 10.4 mmol), 4-amino-2-hydroxybenzonitrile (696 mg, 5.2 mmol) and 37% HCl solution (0.88 mL, 10.4 mmol) in 10% aqueous EtOH solution (20 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 26% yield (293 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[C:10]([F:13])([F:12])[F:11].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20].C1COCC1>CCOC(C)=O>[F:12][C:10]([C:9]1([CH2:14][CH2:15][CH:16]=[CH2:17])[C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[NH:1][C:19](=[O:20])[O:18]1)([F:13])[F:11]
Reactant: C=CCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Temperature: 60 °C
Yield: 61.4 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar, argon inlet and a reflux condenser was added (+/-) 2-(2-Amino-5-chlorophenyl)-1,1,1-trifluoro-5-hexen-2-ol (4.80 g, 17.16 mmol), 1,1'-carbonyldiimidazole (13.91 g, 85.81 mmol) and dry THF (75 mL). This mixture was heated at 60° C. for 18 h. The cooled reaction mixture was diluted with EtOAc and washed with H2O (3×200 mL) and brine (250 mL). Drying (MgSO4), filtration, removal of the solvent in vacuo, followed by recrystallization from boiling EtOAc-hexane gave 3.22 g of (+/-) 4-(1,1,1,-trifluoromethyl)-4(1-buten-4-yl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white crystalline solid, mp: 165°-166° C. 1H NMR (CDCl3): δ1.99 (m, 1H), 2.09-2.40 (m, 3H), 5.00 (d, 1H, J=1.4 Hz), 5.03 (dd, 1H, J=1.4, 7.9), 5.78 (m, 1H), 6.85 (d, 1H, J=8.6 Hz), 7.21 (br s, 1H), 7.35 (dd, 1H, J=2.2, 8.6 Hz), 9.63 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[CH:5]1.C(OCCN1C2C3C=CC=CC=3N=C(Cl)C=2N=C1)(=[O:25])C1C=CC=CC=1.C(OC(=O)C)(=O)C>>[OH:25][C:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:3][CH2:2][OH:1])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(OCCn1cnc2c(Cl)nc3ccccc3c21)c1ccccc1
Reactant: [O-][n+]1cc2ncn(CCO)c2c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: OCCn1cnc2c(O)nc3ccccc3c21

Procedure:
Using the method of Example 133, 1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-5-oxide prepared by hydrolysis of the compound of Example 120 was reacted with acetic anhydride to provide 4-hydroxy-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18])C(OC)=O.[Cl-].[Li+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 100 °C

Procedure:
2-(4-nitro-2chlorophenyl)-malonic acid dimethyl ester was dissolved in DMSO, then lithium chloride (0.759 g), and water (0.15 mL) were added. The mixture was heated to 100° C. for 3h. The reaction was cooled and the product purified by chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to give the title compound as a yellow oil (1.77 g).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C1COCC1>[N+:19]([C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=1)[CH2:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)([O-:21])=[O:20]
Reactant: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CN2CCOCC2)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 38 %

Procedure:
To a solution of morpholin-4-yl-(3-nitro-5-(trifluoromethyl)phenyl)methanone (457 mg, 1.5 mmol) in THF (5 mL) was added dropwise a solution of borane tetrahydrofuran complex solution (3.1 mL, 3.1 mmol) at ambient temperature and the mixture was heated under reflux for 30 minutes, then cooled. The solvent was evaporated. Aqueous HCl (5 mL) was added and the resulting mixture was heated at 100° C. for 1 hour, then cooled and extracted with ether. The acidic aqueous layer was separated, basified to pH 8 with NaOH and extracted with ether. The ether solution was dried over anhydrous Na2SO4. Evaporation of ether provided 168 mg (0.57 mmol) of 4-(3-Nitro-5-trifluoromethylbenzyl)morpholine (38%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2[O:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:7][CH:6]=1)(C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2[O:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:7][CH:6]=1
Reactant: CC(C)Oc1ccc(CCCC2OC(=O)NC2=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1NC(=O)C(CCCc2ccc(O)cc2)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of 5-[3-(4-isopropoxyphenyl)propyl]-2,4-oxazolidinedione (1.5 g) in dichloromethane (70 ml) was added dropwise titanium tetrachloride (TiCl4) (4.1 g) at 0° C. The mixture was stirred for one hour at the same temperature. The reaction mixture was poured into ice-water, and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate (MgSO4). The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:4, v/v), 5-[3-(4-hydroxyphenyl)propyl]-2,4-oxazolidinedione (0.755 g, 59%) was obtained. Recrystallization from acetone-hexane gave colorless prisms. Melting point: 132-133° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:40]([CH2:41][CH2:42][OH:43])=[C:39]([CH3:44])[O:38][N:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:43][CH2:42][CH2:41][C:40]3[C:36]([CH3:35])=[N:37][O:38][C:39]=3[CH3:44])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: Cc1noc(C)c1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1CCOc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Reaction time: 18 h
Yield: 41.1 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (50 mg, 0.107 mmol), 2-(3,5-dimethylisoxazol-4-yl)ethanol (75 mg, 0.533 mmol) and Ph3P-resin (139 mg, 0.533 mmol) in THF (2 mL) was added DIAD (0.104 mL, 0.533 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1NNaOH (1.067 mL, 1.067 mmol) in MeOH (2 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(2-(3,5-dimethylisoxazol-4-yl)ethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (25 mg, 0.044 mmol, 41.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.20 (d, J=8.8 Hz, 1H), 7.07-6.92 (m, 3H), 5.75 (s, 1H), 4.17-4.01 (m, 2H), 3.41 (br. s., 1H), 3.17 (s, 2H), 2.79 (t, J=6.2 Hz, 2H), 2.42 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H), 2.17 (d, J=12.5 Hz, 1H), 2.06-2.02 (m, 2H), 1.93 (br. s., 1H), 1.49 (br. s., 1H), 1.29 (br. s., 1H), 1.16 (d, J=13.6 Hz, 1H), 1.11 (s, 9H), 1.01 (d, J=9.9 Hz, 1H), 0.84 (br. s., 3H), 0.61 (br. s., 3H). LCMS (M+H)=564.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C@H:9]([C@@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)[C@@H:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]1.C1(C)C=CC(S(O)(=O)=[O:38])=CC=1.C(=O)(O)[O-].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C@H:9]([C@@H:10]([OH:11])[CH2:14][OH:13])[C@H:8]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C:7]1=[O:38]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CN2C[C@H](NC(=O)OC(C)(C)C)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2[C@@H](O)CO)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 204.8 %

Procedure:
76.8 g (0.176 mol) of t-butyl (3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-azetidinecarbamate are dissolved in 500 ml of tetrahydrofuran and 350 ml of water and the solution is heated to 60° C. for 24 hours with 13.0 g of p-toluenesulphonic acid. The mixture is cooled, neutralized with 10% aqueous potassium bicarbonate solution and evaporated. The residue is taken up in 300 ml of dioxan and treated with 21.8 g (0.1 mol) of di-t-butyl dicarbonate and 7.63 g of potassium carbonate. The mixture is stirred at room temperature for 24 hours and filtered. The solvent is then removed by evaporation. The crude product is recrystallized from acetonitrile. 61.3 g (88%) of t-butyl (3S, 4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-1,2-dihydroxyethyl]-2-oxo-3-azetidinecarbamate are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl.Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([C:31]5[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=5)[CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:11])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Clc1ccncc1
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCN(c2ccncc2)CC1
Yield: 28.5 %

Procedure:
(Method B) A mixture of 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone (471 mg), 4-chloropyridine hydrochloride (225 mg) and triethylamine (405 mg) in ethanol (20 ml) was reacted in a sealed tube at 150° C. for 18 hours. The reaction mixture was concentrated, and the residue was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with dichloromethane. The extract was washed with water and brine, dried and concentrated to obtain a residue, which was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=12:1) and crystallized from a mixture of ethanol and diethyl ether to obtain the title compound (156 mg) as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[C:19]([CH2:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1O)[CH3:9].Cl.[CH3:26][N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28]>C(Cl)Cl>[CH3:26][N:27]([CH2:29][C:30]([O:32][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]([O:22][CH3:23])=[C:19]([CH2:20][CH3:21])[C:10]=1[CH2:8][CH3:9])=[O:31])[CH3:28]
Reactant: CN(C)CC(=O)O
Reactant: CCc1c(CC)c(OC)c2ccccc2c1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1c(CC)c(OC(=O)CN(C)C)c2ccccc2c1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
Triethylamine (3 eq) and dry methylene chloride (150 ml) are introduced to a mixture of 2,3-diethyl-4-methoxynaphthol (1.59 g, 6.5 mmole), dimethylamino acetic acid hydrochloride (2 eq, 1.8 g, 13.0 mmole), dicyclohexylcarbadiimide (2 eq, 2.7 g, 13.0 mmole) and 4-dimethylaminpyridine (1 eq, 2.7 ml, 19.5 mmole), prepared under an argon atmosphere, at room temperature under argon. The resulting suspension is stirred at room temperature for 20 hours under argon, then diluted with 300 ml of methylene chloride. The methylene chloride extracts are washed thoroughly with saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is chromatographed through a silica gel (200 g) flash column and eluted by ether to give 1.48 g (72.2%) of N,N-dimethylamino acetic acid, 2,3-diethyl-4-methoxynaphth-1-yl ester as a yellowish brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:37]5[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=5)[CH2:45][CH2:44]4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: COc1ccc(N2CCN(C(=O)c3ccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)cc3)CC2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=622.01 (M+H+); retention time=0.92 minutes.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:10]1[C:1]2([CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]2)[CH2:7][CH2:8][CH2:9]1
Reactant: OCCCC1=CCC=CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C1=CCC2(CC1)CCCO2
Temperature: 115 °C
Yield: 76 %

Procedure:
This crude 3-(1,4-cyclohexadienyl)propan-1-ol thus obtained was divided into two batches. Each batch was treated separately with 2.5 g of p-toluenesulfonic acid. The pressure was lowered to 12 mmHg and the pot immersed in an oil bath heated to 115° C. After about 0.3 hr distillation through a short vacuum jacketed vigreaux column at reduced pressure began and continued at a steady rate as cyclization proceeded. A total of 105.4 g (76% yield) of the 1-oxaspiro[4.5]dec-7-ene was obtained as a water white liquid, bp 79°-81° C. (12 mmHg). The NMR spectrum was identical to that for the same compound described in Example 1 above, step E.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[S:38]([CH3:37])(=[O:40])=[O:39])[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3)cc2OCc2ccccc2)S1(=O)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3S(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from 5-[2-benzyloxy-4-((E)-2-piperidin-2-yl-vinyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 92, step A) and methanesulfonyl chloride analogous to Example 192, step B.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[CH2:4]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4]
Reactant: C=C(CCl)c1ccc([N+](=O)[O-])cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(CCl)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 51.3 g (0.26 Mol) of 4(1-chloromethyl-ethenyl)-nitrobenzene and 10 g of tris(triphenylphosphine)-rhodium (I) chloride in 1000 ml of dry toluene is hydrogenated at ambient temperature and atmospheric pressure.