Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH3:17][N:18]=[C:19]=[S:20]>C(O)C>[C:1]([NH:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:19]([NH:18][CH3:17])=[S:20])=[CH:14][CH:15]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)NNc1ccc(N)cc1
Reactant: CN=C=S
Solvent: CCO
Product: CCOC(=O)C(=O)NNc1ccc(NC(=S)NC)cc1
Yield: 72.8 %

Procedure:
8.9 g of 1-ethoxalyl-2-(4-aminophenyl)hydrazine and 3.0 g of methyl isothiocyanate were added to 75 ml of ethanol, followed by refluxing for 3.5 hours under heating. The refluxed product was left to stand for cooling and the precipitated crystal was collected by filtration, washed with ethanol and then dried to obtain 8.6 g of 1-ethoxalyl-2-[4-(3-methylthioureido)phenyl]hydrazine (intermediate A) having a melting point of 168°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:12]=[C:11]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=O.Cl.[NH2:23][OH:24].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:12]=[C:11]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[N:23][OH:24]
Reactant: O=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
To a mixture of 5.58 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal and 50 ml of pyridine was added 1.25 g of hydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 2.44 g (yield, 41%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal oxime, nD23.4 1.5600.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([O:18]CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:16]=[O:18])[CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Reactant: CCOCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Temperature: 25 °C
Yield: 94 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl chroman, (0.5 g, 1.865 mmol) in anhydrous dichloromethane (5 mL) was treated with a 1M solution (1.86 mL, 1.86 mmol) of titanium tetrachloride in dichloromethane followed by α,α-dichloro methyl ether (0.214 g, 1.865 mmol). The reaction mixture was allowed to warm to ambient temperature for 4 h. The reaction mixture was diluted with diethyl ether, washed with brine (×1) and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane to afford the title compound as a yellow solid (0.52 g, 94%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH2:26][CH2:27][F:28])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[F:28][CH2:27][CH2:26][N:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1
Reactant: FCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2nn(CCF)cc2-c2ccncc2)cc1
Reaction time: 18 h
Yield: 91.6 %

Procedure:
Pd/C (1 g) was added to a solution of Intermediate 3B, 4-(3-(4-(benzyloxy)phenyl)-1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyridine (2.1 g) in EtOAc/EtOH (30 mL+30 mL). The mixture was stirred in autoclave at 2.5 atm H2 for 18 h. Pd/C was filtered off and the filtrate was concentrated under reduced pressure to yield the crude product. Purification by flash column chromatography afforded the pure product, 4-(1-(2-fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenol (1.46 g, 92%). 1H NMR (300 MHz, methanol-d4) δ 8.37 (dd, J=4.6, 1.6, 2H), 8.08 (s, 1H), 7.31 (dd, J=4.6, 1.7, 2H), 7.27-7.22 (m, 2H), 6.83-6.78 (m, 2H), 4.81 (dt, J=47.1, 4.7, 2H), 4.49 (dt, J=26.6, 4.7, 2H). MS (DCI—NH3) m/z=284 (M+H)+. (Note: Alternative preparation experimental details published in Journal of Medicinal Chemistry 2011, 54, 5820-5835, Compound 8b)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([O:11][CH:12]([CH2:23][CH3:24])[C:13]([NH:15][C:16]([CH3:22])([CH3:21])[C:17]#[C:18][CH2:19][CH3:20])=[O:14])[CH:8]=[N:9][CH:10]=1)=[O:4].[OH-].[Na+]>CC(O)C.O>[C:3]([C:5]1[CH:6]=[C:7]([O:11][CH:12]([CH2:23][CH3:24])[C:13]([NH:15][C:16]([CH3:22])([CH3:21])[C:17]#[C:18][CH2:19][CH3:20])=[O:14])[CH:8]=[N:9][CH:10]=1)([OH:4])=[O:2]
Reactant: CCC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C(=O)O)c1
Reaction time: 1.5 h

Procedure:
The product from Stage 2 (2.18 g) was dissolved in propan-2-ol (25 ml) and a solution of sodium hydroxide (0.28 g) in water (10 ml) was added at ambient temperature. The mixture was stirred for 1.5 hours, stored at ambient temperature for 18 hours and evaporated under reduced pressure to remove the propan-2-ol. The residual aqueous solution was diluted with water, washed with ethyl acetate and the aqueous phase was acidified with hydrochloric acid. The acidic aqueous phase was extracted with ethyl acetate (three times) and the extracts were combined, washed with water (twice), dried over magnesium sulphate and evaporated under reduced pressure to give a solid. The solid was washed with a small volume of diethyl ether then filtered from solution to give the required product as a colourless solid; 1.47 g; m.p. 162–164° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([O:21][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:20])=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Reaction time: 18 h
Yield: 79 %

Procedure:
Benzyl bromide (9.98 g, 58.3 mmol) was added to a solution of 4-(4-bromophenyl)-4-oxobutanoic acid (15.0 g, 58.3 mmol) and K2CO3 (3.5 g, 58.3 mmol) in DMF (300 mL) and stirred for 18 hours. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (500 mL). Sat'd NaHCO3 soln (20 mL) was added and the aqueous layer extracted with ethyl acetate (2×) and the combined organic layers were washed with brine and dried and filtered. Concentration gave Example J5, benzyl 4-(4-bromophenyl)-4-oxobutanoate 16 g (79%) which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.35-7.34 (m, 5H), 5.14 (s, 2H), 3.27 (t, J=6.7 Hz, 2H), 2.81 (t, J=6.7 Hz, 2H). HRMS: Anal. C17H16BrNO3 Calcd. 347.0277; found: 347.0283 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].Br[CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[I-].[K+]>CN(P(N(C)C)(N(C)C)=O)C>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C@H:13]([C:14]([OH:16])=[O:15])[CH:17]([CH3:19])[CH3:18])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CC(C)C(Br)C(=O)O
Reactant: COc1cc(N)cc(OC)c1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(N[C@H](C(=O)O)C(C)C)cc(OC)c1

Procedure:
A mixture of 3,5-dimethoxyaniline (2.1 g), the m-phenoxybenzyl ester of α-bromoisovaleric acid (1.0 g), potassium iodide (72.9 mg) and 5 ml of HMPT is heated overnight at 70°-80°. The reaction is then worked up by partition between 100 ml of 2 N sulfuric acid and 100 ml of ether. The aqueous phase is extracted with ether and then the combined ether phases are washed with 2 N sulfuric acid, saturated sodium bicarbonate and brine, dried over potassium carbonate, filtered and evaporated. The residue is subjected to prep. TLC eluting with ether/hexane to yield the m-phenoxybenzyl ester of N-(3,5-dimethoxyphenyl)valine. MS m/e 435.2 (M+, 11.7), 208.1 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[C:11]([CH2:16][OH:17])[CH:12]=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[O-:21][Mn](=O)(=O)=O.[K+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([CH3:15])=[N:13][CH:12]=[C:11]([C:10]=2[CH3:18])[C:16]([OH:21])=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ncc(CO)c(C)c1Oc1ccnc(Cl)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ncc(C(=O)O)c(C)c1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
(5-(2-chloropyridin-4-yloxy)-4,6-dimethylpyridin-3-yl)methanol (5.00 g, 18.9 mmol) was charged with NaOH (0.1N in H2O, 19 ml, 1.9 mmol). 3% Aqueous KMnO4 (119 ml, 22.7 mmol) was then added. The reaction stirred at room temperature overnight. The solution was diluted with dichloromethane, filtered through celite, and acidified with citric acid. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were dried and concentrated to give 5-(2-chloropyridin-4-yloxy)-4,6-dimethylnicotinic acid (2.66 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]#[CH:12])=[CH:5][C:4]=1[O:13][CH3:14].[Li]CCCC.CON(C)[C:23]([C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24].[NH4+].[Cl-]>C1COCC1>[CH3:14][O:13][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[O:9][CH2:10][C:11]#[C:12][C:23]([C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24]
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: C#CCOc1ccc(OC)c(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(OCC#CC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a THF (50 mL) solution of 1,2-dimethoxy-4-(prop-2-yn-yloxy)benzene (2.118 g), n-BuLi (4.0 mL, 2.64 N hexane solution) was added dropwise at −78° C. and the resulting mixture was stirred at the same temperature for 30 minutes; the reaction mixture was then added dropwise to a solution of (S)-t-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.578 g) in THF (100 mL) at −78° C. and, after stirring at the same temperature for an hour, temperature was raised to room temperature over an hour. The reaction mixture was added to a saturated aqueous solution of NH4Cl (300 mL) to separate the organic layer, which was washed with a saturated aqueous solution of NH4Cl (100 mL), dried (Na2SO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (2.479 g, pale brown oil.)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1>>[F:5][C:4]([F:6])([CH:3]([F:7])[C:2]([F:9])([F:8])[F:1])[CH2:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(C)c1
Reactant: FC(F)=C(F)C(F)(F)F
Product: Cc1cccc(CC(F)(F)C(F)C(F)(F)F)c1
Yield: 70 %

Procedure:
Meta-xylene and hexafluoropropene (3:1 molar ratio), heated at 290° for 3 days, gave 3-(2,2,3,4,4,4-hexafluorobutyl)toluene: ##STR14## in 70% yield based on hexafluoropropene consumed.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(N(CC)CC)C>C(O)C>[C:15]1(=[O:24])[N:14]([CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[2-(bromo)ethyl]phthalimide (5.59 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 3 hours and heated at reflux for 4 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 3.95 g of the desired product (61.1%, yellow crystals).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[OH-:13].[NH4+].OO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([NH2:12])=[O:13])[CH2:9][CH2:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: N#CC1(c2cncc(Br)c2)CC1
Agent: OO
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)C1(c2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(5-Bromo-pyridin-3-yl)-cyclopropanecarbonitrile (150 mg, 0.672 mmol) is dissolved in THF (1.5 mL) in a reaction vial. Ammonium hydroxide (1 mL) is then added. Hydrogen peroxide (30% aq solution, 0.5 mL) is added slowly. The mixture is stirred at room temperature for 4 h. The volatiles is evaporated to afford 1-(5-bromo-pyridin-3-yl)-cyclopropanecarboxylic acid amide (157.5 mg, 97% crude yield).
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([OH:26])=O)[CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1([CH3:17])[CH2:16][CH2:15]1)=[N:5]2.CC[N:29](C(C)C)C(C)C.N>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[C:3]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH2:29])=[O:26])[CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1([CH3:17])[CH2:15][CH2:16]1)=[N:5]2
Reactant: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C)[nH]3)c2nc1NC1(C)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2ccc(F)c(-c3cc(C(N)=O)c(C)[nH]3)c2nc1NC1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxylic acid (417c) (0.119 g, 0.336 mmol), 0-(˜7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium-hexafluorophosphate (GenScript Corporation, 0.160 g, 0.420 mmol), DIPEA (0.146 mL, 0.839 mmol), in DMF (1.679 mL) was stirred at RT for 5 min before addition of ammonia (2.0 M solution in MeOH, Sigma Aldrich, 0.336 mL, 0.672 mmol). The resulting mixture was stirred at RT overnight. Reaction mixture was diluted with DCM and washed with water and brine to remove DMF. Purification by Biotage (0-100% EtOAc/hexanes then 30-100% EtOAc:EtOH(3:1)/hexanes) produced desired product. The residue was diluted with DCM and re-washed two times with alternating water and brine washes to remove DMF and provide 5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxamide (0.031 g, 0.88 mmol, 26% yield). 1H NMR (300 MHz, MeOH) δ ppm 0.84-0.94 (m, 4H) 1.56 (s, 3H) 2.38 (s, 3H) 2.55 (s, 3H) 7.01-7.17 (m, 2H) 7.25-7.35 (m, 1H) 7.37-7.47 (m, 1H) 12.84-13.00 (m, 1H). m/z (ESI, +ve) 354.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:17](C=O)C>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:17])=[O:9])=[N:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ncc(Br)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To 5-bromo-thiazole-2-carboxylic acid (0.267 g, 0.128 mmol) suspended in dry dichloromethane (30 mL) are added oxalyl chloride (0.22 mL, 0.257 mmol) and a drop of DMF. The reaction is stirred for 1 hour at room temperature. The solvent is evaporated and the resultant crude is dissolved in 7M NE3 in MeOH. The reaction mixture is stirred overnight at room temperature. After evaporation of the solvent, the residue is dissolved in dichloromethane and washed with 1M NaOH. The organic phase is dried over MgSO4, filtered and evaporated. The residue is purified by silica gel column chromatography eluting with 95:5 DCM:MeOH to give the title compound (33.8 mg, 25%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]Cl)=[CH:3][CH:2]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:11]=[N+:12]=[N-:13])=[CH:3][CH:2]=1
Reactant: ClCCCc1ccncc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCCc1ccncc1
Temperature: 65 °C

Procedure:
A solution of 2-3 (7 g, 41.2 mmol) in DMSO (150 mL) was treated with sodium azide (2 g, 45.3 mmol) and heated to 65° C. for 72 h. The solution was diluted with EtOAc, washed with H2O and saturated NaHCO3. The H2O washing was basified to pH11 and extracted with EtOAc. The organic layers were combined, dried with brine and MgSO4, filtered and evaporated to give 2-4 as a yellow oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@@H:23](O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@H:23]([S:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(=O)Cc1ccc(S)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(S[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Yield: 18.6 %

Procedure:
20.2 g of ethyl 4-mercaptophenylacetate was dissolved in 450 ml of tetrahydrofuran. With ice cooling and with stirring, 21.0 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine, 29.4 g of triphenylphosphine and 19.5 g of diethyl azodicarboxylate were added to the above solution. The thus prepared mixture was stirred at room temperature for 18 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent, thereby obtaining 7.0 g of ethyl 2-[4[-((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)thio]phenyl]acetate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22]([CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:27])[CH3:20]
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc2c(c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a suspension of 7-hydroxy-tetralone (0.870 g, 5.3 mmol) and K2CO3 (5 g, excess) in DMF (20 mL) was added ethyl-4-bromobutyrate (0.770 mL, 5.3 mmol) at room temperature and under argon atmosphere. The reaction mixture was stirred at room temperature for ˜16 hours before being poured on ice. The aqueous solution was extracted in ethyl acetate, washed with water, and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate-hexane (2:8) as eluent to give 7-(3-ethoxycarbonylpropoxy)-1-tetralone (1.180 g, 80%): mp 62-63° C., 1H NMR (500 MHz, CDCl3): δ 1.26 (t, J=7.0 Hz, 3H), 2.08-2.14 (m, 4H), 2.48-2.51 (dd, J=7.00 and 7.5 Hz, 2H), 2.62-2.64 (dd, J=6.0 and 6.5 Hz, 2H), 2.88-2.90 (dd, J=6.0 and 6.5 Hz, 2H), 4.02-4.05 (dd, J=6.0 and 6.5 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 7.03-7.05 (dd, J=3.0 and 8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.49 (d, J=3.0 Hz, 1H). HFABMS m/z 277.1436 (calc for C16H20O4, MH+, 277.1440).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][C:7](=O)[C:6]=2[CH:16]=1.[CH2:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH:8]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([CH2:17][CH3:18])[CH2:20][CH2:21]3)[C:6]=2[CH:16]=1
Reactant: O=C1Cn2cccc2Sc2ccc(Cl)cc21
Reactant: CCN1CCNCC1
Product: CCN1CCN(C2=Cn3cccc3Sc3ccc(Cl)cc32)CC1

Procedure:
Starting from 7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-one (0.19 g, 0.76 mmol) and N-ethylpiperazine (0.70 mL, 6.13 mmol), the title compound was obtained following the above described procedure for (1). After purification, 0.19 g of the desired product were obtained as a white solid (yield 74%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:22]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[C:26]([F:35])[CH:25]=3)[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:11])=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:22]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[C:26]([F:35])[CH:25]=3)[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:11])=[N:7][CH:8]=1)=[O:1]
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)Nc3ccc(CO)cn3)cc3c2CC(C)(C)O3)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)Nc3ccc(C=O)cn3)cc3c2CC(C)(C)O3)cc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-(4-Dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (5-hydroxymethyl-pyridin-2-yl)-amide (145) (88 mg, 0.18 mmol) in 3 mL CH2Cl2 was added Dess-Martin periodinane (93.4 mg, 0.22 mmol) at 0° C. The mixture was stirred at 0° C. for 1.5 hr. The reaction was quenched with water, extracted with 3×CHCl3. The combined organic layer was dried with Na2SO4 and concentrated. The resulting oil was taken into the next step without further purification. LCMS for C26H24FN3O5 m/z 478.20 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH:15]=3)[N:10]([CH3:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Clc1ccc(-c2n[nH]c3cc4ccccc4cc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1nc(-c2ccc(Cl)cc2)c2cc3ccccc3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 14 g of 3-(p-chlorophenyl)-1H-benz[f] indazole dissolved in 150 ml. dry dimethylacetamide under nitrogen is added 3 g. of a 57% suspension of sodium hydride in mineral oil. The reaction mixture is stirred at room temperature for 1 hour and then 5 ml. of methyl iodide is added. Stirring is continued for 2 hours then the mixture is poured on ice-water, and the precipitate recovered by filtration. The precipitate is recrystallized from ether to yeild the title compound, m.p. 157°-159°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)=[CH:6][C:5]([F:20])=[CH:4][N:3]=1.[ClH:21]>O1CCOCC1>[ClH:1].[ClH:21].[Cl:1][C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:6][C:5]([F:20])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(F)cnc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cnc(Cl)c([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a dioxane (5 mL) solution of (R)-tert-butyl 2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidine-1-carboxylate (500 mg, 1.66 mmol) was added HCl (4 N dioxane, 20 mL), followed by stirring at ambient temperature overnight. The mixture was concentrated and treated with Et2O, then vacuum-dried, to provide the product as a white solid (0.36 g, 80% yield). MS (apci) m/z=201.1 (M+H). The enantiomeric excess (ee %) of the product was determined to be >92% according to the method described in Preparation A.