Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:9][OH:10])=[O:6]>C1COCC1>[F:18][C:13]1[CH:12]=[C:11]([CH:8]2[NH:7][C:5](=[O:6])[CH2:4][O:10][CH2:9]2)[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: O=C(CCl)NC(CO)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(c2ccc(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a suspension of sodium hydride (0.29 g, 11.39 mmol) in 48 mL THF was added a solution of 2-chloro-N-[1-(3,4-difluoro-phenyl)-2-hydroxy-ethyl]-acetamide (2.6 g, 10.4 mmol) in 48 mL THF dropwise via a dropping funnel at −25° C. over 20 min. After the addition was over, the cooling bath was removed and the reaction mixture was stirred at room temperature for 8 hours. TLC analysis indicated a complete disappearance of the starting material. The reaction was quenched by adding a few crystals of ice. It was extracted thoroughly with EtOAc (3×30 mL) and was washed with brine. The organic layer was separated and dried over MgSO4. The organic layer was filtered and the solvent was removed in vacuo. The residue was suspended in EtOAc and the white solid was collected via filtration which was found to be 5-(3,4-difluoro-phenyl)-morpholin-3-one (0.8 g, 38% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:21]([C:20]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:19]=4[O:18][CH3:17])=[O:22])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: COc1cc(C)ccc1C(=O)O
Product: COc1cc(C)ccc1C(=O)N1CC2CN(c3nc(C)cc(C)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 23 and 2-methoxy-4-methylbenzoic acid. MS (ESI): mass calculated for C21H26N4O2, 366.21; m/z found 367.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.13 (d, J=7.6, 1H), 6.77 (d, J=7.6, 1H), 6.70 (s, 1H), 6.28 (s, 1H), 4.00-3.40 (m, 11H), 3.27-2.85 (m, 3H), 2.41-2.19 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.[H-].[Na+].CC(N(C)C)=O.C([Li])CCC>O1CCCC1>[CH3:38][N:14]1[C:15]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]2[N:4]=[CH:3][CH:2]=[CH:7][N:6]=2)=[N:13]1
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncccn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 5.8 %

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3, 100 mg) in anhydrous tetrahydrofuran (2 ml) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 18 mg), followed by dimethyl acetamide (0.5 ml). The mixture was cooled to −78° C. and n-butyl lithium (1.6 M in hexanes, 0.1 ml) was added dropwise under an atmosphere of nitrogen. The yellow solution was allowed to stir at −78° C. for 20 minutes. 1.25 ml of this solution was withdrawn by syringe and added dropwise to a mixture of ether (10 ml) and water (10 ml). The aqueous layer was extracted with ether (3×10 ml). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ethyl acetate:hexane (2:1) to yield the title compound as a white solid (5 mg).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24](Cl)=[C:23]1[C:18]([CH:19]=[CH:20][C:21]([O:29][CH3:30])=[CH:22]1)=[N:17]2.C1(C)C=CC=CC=1>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[Cl:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[C:23]1[C:18]([CH:19]=[CH:20][C:21]([O:29][CH3:30])=[CH:22]1)=[N:17]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
To a solution of sodium (1.3 g, 52 mmol) in ethanol (50 mL) was added diethyl malonate (8.8 g 55 mmol) followed by 6,9-dichloro-2-methoxyacridine (9.68 g, 35 mmol) and toluene (5 mL). The mixture was heated to reflux for 24 h, diluted with aqueous potassium carbonate, extracted with ethyl acetate, dried, and concentrated in vacuo to give solid which was purified by flash column chromatography (silica gel, 5-12% methanol:dichloromethane) to give the title compound. MS(ES) m/e 402.2 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[CH2:13]([C:20]1[O:24][CH:23]=C(CO)[CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][C:10]1[CH:21]=[C:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:24][CH:23]=1)=[O:7])=[CH2:2]
Reactant: OCc1coc(Cc2ccccc2)c1
Reactant: C=CC1CC1(C#N)C(=O)OCC
Product: C=CC1CC1(C#N)C(=O)OCc1coc(Cc2ccccc2)c1
Yield: 85.9 %

Procedure:
In a manner similar to that described above, a transalcoholysis reaction was carried out using ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate and (5-benzyl-3-furyl)carbinol. The ratio of reactants, catalyst level, and reaction temperature employed were the same as indicated in Example II. (5-Benzyl-3-furyl)methyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was obtained in 85.9% yield and purified by separation using the liquid chromatographic procedure. The structure of the purified (99.4%) product was confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20]1.O>CS(C)=O>[CH3:12][C:4]1[CH:3]=[C:2]([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cn(-c2cc(C)nc3ccccc23)c2ncccc12
Temperature: 120 °C
Yield: 17 %

Procedure:
5.5 g (31 mmol) of 4-chloro-2-methylquinoline and 8.9 g (65 mmol) of potassium carbonate were added to 4.6 g (26 mmol) of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate in 93 cm3 of dimethyl sulfoxide under argon. The reaction mixture was heated at a temperature in the region of 120° C. for 16 h, then it was cooled to a temperature in the region of 20° C. and treated with 250 cm3 of water. The aqueous phase was extracted with 250 cm3 and then 125 cm3 of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with dichloromethane. The fractions comprising the expected product were combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.4 g of methyl 1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate were thus obtained in the form of an orange crystalline solid melting at 179° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.[H-].[Na+].C(O)(=O)C>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (6.0 g) and 4-fluorobenzonitrile (5.4 g) were dissolved in tetrahydrofurane (70 ml ), and 60% sodium hydride in oil (1.4 g) was added to the solution under ice-cooling with vigorous stirring. The reaction mixture was stirred at room temperature for 18 hours and poured into ice-cold water (0.5 l). The aqueous mixture was neutralized with acetic acid, and the crystals which separated out were collected by filtration to give 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzonitrile (7.0 g, 77.5%). Recrystallization from ether-hexane afforded colorless prisms, m.p. 119°-120° C. Elemental analysis for C19H16N2O2 ; Calcd: C, 74.98; H, 5.30; N, 9.20. Found: C, 74.90; H, 5.01; N, 9.28.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[S:27]1(=[O:37])=[O:36]>>[O:36]=[S:27]1(=[O:37])[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[C:30](=[O:31])[N:26]1[CH2:25][CH2:24][CH2:23][CH2:22][N:17]1[CH2:18][CH2:19][CH:14]([N:10]2[C:9]3[CH:20]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=3[O:12][C:11]2=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)(C)c1ccc2oc(=O)n(C3CCNCC3)c2c1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Product: CC(C)(C)c1ccc2oc(=O)n(C3CCN(CCCCN4C(=O)c5ccccc5S4(=O)=O)CC3)c2c1

Procedure:
From the hydrochloride salt of 4-(5-tert-butyl-2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 8.07 (dd, J=6.6, 2.25 Hz, 1H), 7.88 (m, 3H), 7.19 (s, 1H), 7.11 (s, 2H), 4.17 (tt, J=12.21, 3.66 Hz, 1H), 3.85 (t, J=7.14 Hz, 2H), 3.09 (d, J=10.85 Hz, 2H), 2.46 (t, J=7.38 Hz, 2H), 2.36 (dt, J=12.15, 3.5 Hz, 2H), 2.13 (dt, J=10.89, 1.27 Hz, 2H), 1.91 (m, 4H), 1.66 (m, 2H), 1.342 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C@H:11]([OH:15])[C:12]([OH:14])=[O:13])[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO[C:18](OC)([CH3:20])[CH3:19]>CC(C)=O.[Cu](Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C@H:11]2[C:12](=[O:14])[O:13][C:18]([CH3:20])([CH3:19])[O:15]2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H](O)[C@@H](CC1CCCC1)C(=O)O
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CC1(C)OC(=O)[C@H]([C@@H](CC2CCCC2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2R,3S)-2-(cyclopentylmethyl)-3-hydroxysuccinic acid (18.97 g, 87.73 mmol; 1.0 eq.) in acetone (300 mL) was added 2,2-dimethoxypropane (21.6 mL, 175.46 mmol, 2.0 eq.) and copper (II) chloride (1.18 g; 8.77 mmol, 0.1 eq.). The resulting reaction mixture was stirred for 16 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3 (200 mL). Activated charcoal (10 g) was added and the resulting mixture was stirred at RT for 30 minutes. Filtration on a pad of celite gave the title product as yellowish oil. Purification by flash chromatography (Si60; 40-60 microns) eluting with Heptane/MTBE 60/40 gave the title product (16.30 g; 72.5%) as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-Bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (281 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (310 mg, 54%). MS (ISP) 565.4 [(M+H)+]; mp 161-162° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].CN1CCCC1=O>O>[N:18]([C:13]([CH3:15])([CH3:14])[C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])=[N+:19]=[N-:20]
Reactant: CC(C)(Br)C(=O)NCCOCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(N=[N+]=[N-])C(=O)NCCOCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of the crude amide (104 g), sodium azide (23.6 g) and N-methyl-2-pyrrolidone (500 ml) was heated at 50° C. for 22 h. After cooling to room temperatur water was added and the resulting mixture was extracted with diethyl ether (2×400 ml). The combined organic phases were washed with brine (3×500 ml) and dried (Na2 SO4). Evaporation of the solvents in vacuo gave 2-azido-N-(2-benzyloxyethyl)-2-methylpropionamide as an oil:78 g.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(OC(C)C)(C)C.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:20](=[O:21])[CH2:19][CH2:18][Cl:17]
Reactant: O=C(Cl)CCCl
Reactant: Cc1cccc(C)c1N
Solvent: CC(C)OC(C)C
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CCCl
Reaction time: 3 h
Yield: 59.7 %

Procedure:
A 2 l three-necked flask, is charged with 121.8 g of 2,6-dimethylaniline, 300 ml of isopropyl ether and 150 ml of water. 126.5 g of 3-chloropropanoyl chloride are added at a rate such that the internal temperature is between 5 and 10° C. At the end of the addition, the reaction medium is stirred for 3 h. The precipitate formed is filtered off with suction, washed with isopropyl ether and then with water and finally dried. 126 g of white crystals are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[C:29]2[CH:30]=[CH:31][C:32]([OH:37])=[C:33]([CH2:34][CH2:35][CH3:36])[C:28]=2[O:27][N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:39][C:24]([F:23])([F:38])[C:25]1[C:29]2[CH:30]=[CH:31][C:32]([O:37][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:15]=[C:14]4[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]4)=[CH:8][CH:7]=3)=[C:33]([CH2:34][CH2:35][CH3:36])[C:28]=2[O:27][N:26]=1
Reactant: CCOC(=O)C1(CC)CCc2ccc(OCCCBr)cc2O1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2)OC(CC)(C(=O)OCC)CC3)ccc2c(C(F)(F)F)noc12
Temperature: 70 °C
Yield: 85 %

Procedure:
To a 2 ml DMF solution of ethyl 7-(3-bromopropoxy)-2-ethylchromane-2-carboxylate (40 mg, 0.108 mmol) and 3-trifluoromethyl-7-propyl-6-hydroxybenzisoxazole (U.S. Pat. No. 6,090,836) (29 mg, 0.118 mmol) was added cesium carbonate (39 mg, 0.12 mmol). The resulting suspension was heated to 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and water. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 20% AcOEt/hexanes gave the title compound as a pale yellow oil 49 mg (85%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[C:11]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[C:12]=1[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:20]=1.II>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:17][N:14]1[C:13](=[O:18])[C:12]2[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:20]=3[C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[O:1][C:2]=3[C:11]=2[C:15]1=[O:16]
Reactant: CN1C(=O)C(C2=COc3ccccc3O2)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Agent: II
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1c(=O)c2c3oc4ccccc4oc3c3c(c4ccccc4n3C(=O)OC(C)(C)C)c2c1=O

Procedure:
218.1 μmol of the compound obtained in Step A above and 5.91 mmol of double-sublimed iodine are dissolved in 500 ml of toluene inside the cell of an irradiation apparatus. After irradiating for 30 minutes, with stirring, the reaction mixture is cooled and then diluted with ethyl acetate. Washing with 80 ml of 20% aqueous sodium thiosulphate solution is carried out until the organic phase is decolourised. The aqueous phase is extracted with ethyl acetate three times, and then the organic phases are combined and directly concentrated in vacuo. A brown, semi-oily, semi-solid residue is collected. The procedure is repeated a further five times in the same manner, using the same amounts. The crude reaction products of the six procedures are combined. Washing with ethyl acetate is carried out on the six crude reaction products, which are then filtered. The filtrate is evaporated and then taken up in methanol, filtered, rinsed with methanol and then dried in vacuo, allowing the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2ccc(F)c(Cl)c2c(=O)o1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)c(Cl)c2C(=O)N2CCC[C@@H]12

Procedure:
3.3 g (0.015 mol) of 6-chloro-5-fluoroisatoic acid anhydride and 2 g (0.017 mol) of L-proline in 7.5 ml of dimethylformamide are heated to 120° for 2 hours, cooled, treated with 12 ml of distilled water and the precipitated brown crystals are filtered off. By recrystallization of the crude product from acetone/hexane there is obtained (S)-6-chloro-7-fluoro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 217°-219°.
Reaction SMILES: B(F)(F)F.[C:5]([OH:8])(=O)[CH3:6].[C:9]1([CH2:15][C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:9]1([CH:15]([C:5](=[O:8])[CH3:6])[C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O
Reactant: CC(=O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(C(C)=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
Boron trifluoride-acetic acid (36%, 34.8 grams) was added with stirring dropwise to a solution of phenylacetone (4.46 grams), acetic anhydride, and para-toluenesulfonic acid (0.6 grams) in a water bath at room temperature. After stirring over night, a solid precipitate formed which was collected and washed with water and then refluxed in 100 ml water and sodium acetate (9.0 grams) for 2-3 hours. The original reaction mixture was also heated with 200 ml water and sodium acetate (13.5 grams) for the same period. Both mixtures were separately extracted with ether and then washed with saturated sodium bicarbonate solution to remove any acid. The ether portions were dried and then evaporated in vacuo leaving an oil which solidified, yield 1.4 grams, m.p. 40°-52° C.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[CH:22][CH:21]=1.[OH-].[Na+]>Cl.CN1C(=O)CCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: NC(=O)CCCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)CCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 37.3 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol), 4-(4-aminophenyl)butanamide (0.071 g, 0.40 mmol) and conc. HCl (2 drops) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 2 h. The reaction mixture was cooled, diluted with water (5 mL) then treated with 2M aqueous sodium hydroxide until pH˜8 affording a solid. The solid was isolated by filtration and purified by chromatography on silica using dichloromethane/methanol (10:0 to 19:1) as eluent followed by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford 4-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)butanamide (0.050 g, 37%) as a white solid. MW=405.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.07 (s, 1H), 7.91 (t, J=2.0 Hz, 1H), 7.74 (dt, J=7.5, 1.5 Hz, 1H), 7.46-7.38 (m, 2H), 7.25 (br s, 1H), 7.22-7.15 (m, 5H), 6.71 (br s, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.08 (quin, J=7.5 Hz, 4H), 1.79 (quin, J=7.5 Hz, 2H); ESI MS m/z 406 [M+H]+. Treatment with 1.25M HCl in methanol afforded the title compound (0.053 g, 99%) as an off-white solid. MW=442.38. M.p. 108-111° C. 1H NMR (DMSO-d6, 500 MHz) δ 11.91 (br s, 1H), 8.84 (br s, 1H), 7.91-7.88 (m, 1H), 7.74-7.69 (m, 1H), 7.54-7.47 (m, 2H), 7.27-7.22 (m, 5H), 7.11 (br s, 1H), 6.72 (br s, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz, 2H), 2.09 (t, J=7.5 Hz, 2H), 1.80 (quin, J=7.5 Hz, 2H); ESI MS m/z 406 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11]
Reactant: COc1ccc(OC)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(OC)cc1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
2,5-dimethoxy toluene (6.0 g) was dissolved in acetic acid (20 mL). To the solution, a solution of fuming nitric acid (d=1.50, 4.32 g) in acetic acid (10 mL) was added dropwise at 40° C. over a period of 5 min. The mixture was stirred at 40° C. for 30 min. The reaction mixture was then allowed to cool to room temperature, which was stirred for another 30 min. Then the reaction mixture was diluted with cold water (300 mL). The resulting precipitate was filtered washed with cold water (100 mL) and dried under reduced pressure to afford the title compound (7.5 g).
Reaction SMILES: [CH3:1][C:2]([S:9][CH3:10])([CH3:8])[C:3]([O:5]CC)=O.[C:11](#[N:13])[CH3:12]>>[CH3:8][C:2]([S:9][CH3:10])([CH3:1])[C:3](=[O:5])[CH2:12][C:11]#[N:13]
Reactant: CCOC(=O)C(C)(C)SC
Reactant: CC#N
Product: CSC(C)(C)C(=O)CC#N
Yield: 81 %

Procedure:
The title compound was prepared from ethyl 2-methyl-2-(methylthio)propionate and acetonitrile, using a method similar to that of preparation 2, as a colourless oil in 81% yield.