Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C.CO.C1C[O:29][CH2:28]C1>>[CH3:28][O:29][C:9]1[C:8]([C:6]([OH:5])=[O:7])=[C:17]([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)ccc2c1C
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 70 °C
Yield: 66 %

Procedure:
A 2M aq. LiOH sol. (12 ml) was added to a solution of 1.3 g (4.0 mmol) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (synthesis see Example 3 Section a)) in a MeOH/THF mixture (in each case 10 ml) and the solution was subsequently heated to 70° C. for 16 h. The organic solvents were removed as far as possible in a vacuum and the obtained aqueous solution was washed with EtOAc, adjusted to pH 2 with 2M hydrochloric acid and diluted with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 754 mg (2.6 mmol, 66%) 2-methoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:23]=[CH:22][C:21]([CH3:24])=[N:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH:21]([CH3:24])[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2n1
Agent: O=[Pt]=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1CCc2c(ncnc2N2CCN(C(=O)OC(C)(C)C)CC2)N1

Procedure:
A solution of 4-(7-Methyl-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 3.64 mmol), PtO2 (42 mg, 0.18 mmol) in MeOH (40 mL) and TFA (2 mL) was stirred under H2 (1 atm) at room temperature for 4 hours. The catalyst was filtered and the solvent was removed. The residue was subject to column chromatography, eluted by DCM/MeOH (20:1) to give 4-(7-Methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as TFA salt (0.43 g, 27%). 1H NMR (CDCl3, 400 MHz) δ 9.75 (s, 1H), 7.97 (s, 1H), 3.60 (m, 10H), 2.60 (m, 2H), 2.00 (m, 1H), 1.48 (s, 9H), 1.35 (d, J=6.4 Hz, 3H). MS (APCI+) [M+H]+334.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH:7]([C:9](=[O:18])[C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[O:8][C:4]=2[CH:3]=1.S(OC)(O[CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([O:19][CH3:26])=[C:7]([C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[O:18])[O:8][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1ccc(Cl)cc1Cl)C1Oc2cc(Br)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Yield: 27.8 %

Procedure:
To a solution of 6-Bromo-2-(2,4-dichloro-benzoyl)-benzofuran-3-one (3.30 g, 8.55 mmol) in acetone (50 mL) was added dimethyl sulfate (1.19 g, 9.40 mmol) and cesium carbonate (4.18 g, 12.82 mmol). The resulting mixture was heated at 50 deg for 6 hours at which time the reaction mixture was concentrated via rotary evaporation. The resulting mixture was taken up in EtOAc and washed twice with water and one time with a saturated sodium carbonate solution. The organic portion was dried over MgSO4 and then filtered and concentrated. The resultant oil was purified via column chromatography (10% MeOH/Dichloromethane) to provide the title compound (950 mg, 28%). 1H-NMR (CDCl3): δ 8.03 (d, 1H), 7.65 (d, 1H), 7.46 (m, 2H), 7.35 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([O:25]C)=O)=[CH:22][C:12]=2[N:11]=1.[F:29][C:30]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:31]=1[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:32][C:31]3[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:30]=3[F:29])=[O:25])=[CH:22][C:12]=2[N:11]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cc3nc(Nc4c(F)cccc4Cl)n(C)c3c3c2OC(C)(C)C3)c(F)c1
Yield: 20.4 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Step-7 of Intermediate-49, 0.100 g, 0.247 mmol), 2-fluoro-4-methyl aniline (0.046 g, 0.371 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 2.29 (s, 3H), 3.48 (s, 2H), 3.56 (s, 3H), 7.00 (d, J=8.4 Hz, 2H), 7.13-7.30 (m, 4H), 8.29 (t, J=9 Hz, 1H), 9.94 (s, 1H), 10.51 (s, 1H). MS [M+H]+: 497.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:24][C:23]([CH3:38])([CH3:37])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][CH2:27][CH2:28][NH2:29])[CH2:24][C:23]([CH3:38])([CH3:37])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCNC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(NCCN)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1

Procedure:
A solution of the product of Step A (42.9 mg, 0.07 mmol) in 2.5 mL of 20% TFA in CH2Cl2 was stirred at rt for 1 h. The reaction mixture was concentrated to give the product which was used without further purification.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Cl[P:8]1(=[S:18])[O:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[O:9]1>CO>[CH3:12][O:13][P:8]1(=[S:18])[O:4][CH2:1][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[O:9]1
Reactant: O=C([O-])[O-]
Reactant: S=P1(Cl)OCc2ccccc2O1
Agent: [K+]
Solvent: CO
Product: COP1(=S)OCc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
Into a reaction flask was placed 150 ml methanol, 21 g (0.15 moles) potassium carbonate, and 22 g (0.1 moles) of 2-chloro-4H-1,3,2-benzodioxaphosphorin-2-sulfide. The reaction mixture was stirred at room temperature for 2 hours, filtered, and the axcess methanol recovered via reduced pressure. The residue was dissolved in 50 ml chloroform, washed with two portions of water (total of 100 ml), dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue crystallized to yield 19.2 g (92%) of 2-methoxy-4H-1,3,2-benzodioxaphosphorin-2-sulfide having a melting point 50°-53° C. The melting point, IR and NMR spectra of this product were identical to the known insecticide, Salithion. By using corresponding alkanols instead of methanol, the corresponding 2-alkoxy derivatives are obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][N:9]([CH2:11][CH2:12][CH2:13][C:14]1([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[O:22][CH2:21][C:20]2[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=[CH:16][C:15]1=2)C.CC(Cl)OC(Cl)=O.C(N(C(C)C)CC)(C)C>CO>[CH3:8][NH:9][CH2:11][CH2:12][CH2:13][C@:14]1([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[O:22][CH2:21][C:20]2[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=[CH:16][C:15]1=2
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CNCCC[C@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 12.5 °C
Reaction time: 0.5 h

Procedure:
The toluene solution containing citalopram base was mixed with 1,2-dichloromethane (400 lit) and cooled to 10-15° C. A solution of 1-chloro ethyl chloroformate (110.8 Kg, 0.77 kmoles) was added to the reaction mass below 20° C. The reaction mass was further stirred for 30 minutes at 15-20° C. Diisopropylethyl amine (30.24 Kg, 0.23 kmoles) was added to the reaction mixture below 20° C. and further stirred for 30 minutes. The temperature of the reaction mass was raised to 60-65° C. and maintained for 2-3 hrs. The reaction mass was diluted with methanol (320 lit) at 60-65° C., heated further for 2-4 hrs at 60-65° C. and evaporated. The reaction mass was cooled to 25-30° C., diluted with water (480 lit) and stirred for 30 minutes. The phases were separated, aqueous layer was extracted with toluene (2×200 lit) and pH of the aqueous layer was adjusted to 9-10 with ammonia solution (320 lit). Toluene (400 lit) was added and the reaction mass stirred for 30 minutes. The organic layer was separated. Aqueous layer was extracted with toluene (2×200 lit). The combined toluene layer was washed with water, followed by brine. The toluene layer was dried on sodium sulphate, filtered and stirred with charcoal (15 Kg). The reaction mass was filtered and evaporated under reduced pressure to afford the title compound. Yield—140 Kg, 91.5%
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[C:17](=O)[CH2:16][O:15]2)=[CH:10][CH:9]=1.CO>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[O:15][CH2:16][CH2:17][N:18]([C@@H:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH3:21])[CH2:19]2)=[CH:12][CH:13]=1
Reactant: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A borane-tetrahydrofuran complex (1.0M solution in tetrahydrofuran, 510 ml, 510 mm) was added to the ice-cooled solution of (6S)-6-(4-bromophenyl)-4-((1R)-1-phenyethyl)-morpholin-3-one (70.2 g) in tetrahydrofuran (500 ml) over 45 minutes and the solution was stirred at the same temperature for one hour and room temperature for 30 minutes. After careful addition of methanol (60 ml) to the ice-cooled solution, the solvent was removed under reduced pressure and the residue in methanol (750 ml) and 1M aqueous sodium hydroxide (280 ml) was stirred at 80° C. for one hour with addition of 1M aqueous sodium hydroxide (70 ml) in every 15 minutes. The solvents was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium.sulfate. Removal of the solvent yielded (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (65.0 g, 96.3% yield, 2 steps) as white crystals.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][C@@H:9]3[C@@H:14]([CH2:15][C:6]=2[S:5][C:4]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:13]([CH3:16])[CH2:12][C@H:11]([C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH3:21])[CH2:10]3)#[N:2].O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O1CCCC1.Cl[C:53]([O:55][C:56]1[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=1)=[O:54]>C(OCC)(=O)C.O>[C:26]([O:25][C:24]([N:23]([CH3:31])[C:4]1[S:5][C:6]2[CH2:15][C@@H:14]3[C@H:9]([CH2:10][C@@H:11]([C:17]([N:18]([CH2:19][CH2:20][CH3:21])[C:53](=[O:54])[O:55][C:56]4[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=4)=[O:22])[CH2:12][N:13]3[CH3:16])[CH2:8][C:7]=2[C:3]=1[C:1]#[N:2])=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCNC(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(C(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
To a mixture of tert-butyl N-[(4aR*,6R*,8aR*)-3-cyano-8-methyl-6-(propylcarbamoyl)-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-2-yl]-N-methylcarbamate (412 mg) and tetrahydrofuran (5 mL) was added a 1 mol/L sodium hexamethyldisilazide-tetrahydrofuran solution (1.2 mL) at −40° C. After stirring at the same temperature for 20 minutes, 4-nitrophenyl chloroformate (242 mg) was added to the mixture, and then stirred for 1 hour. After warming to room temperature and stirring for 1.5 hours, water and ethyl acetate were added. After the separated organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 80%-100% ethyl acetate/hexane, gradient elution) to give 4-nitrophenyl N-{[(4aR*,6R*,8aR*)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-N-propylcarbamate (405 mg).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][NH:7][C:8]([N:10]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[N:11]1)=[O:9]>C(O)(=O)C>[CH3:6][NH:7][C:8]([N:10]1[C:14]([CH2:15][CH3:16])=[C:13]([Cl:4])[C:12]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:26])([F:27])[F:28])=[CH:20][N:19]=2)=[N:11]1)=[O:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)NC
Solvent: CC(=O)O
Product: CCc1c(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)NC
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
Sulfuryl chloride (0.17 g, 1.2 mmol) was added to a solution of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole-1-carboxamide (0.35 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-4-chloro-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole-1-carboxamide (0.31 g, yield: 80.9%). mp: 88-89° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.30 (t, J=7.4 Hz, 3H), 2.96 (d, J=5.0 Hz, 3H), 3.14 (q, J=7.4 Hz, 2H), 6.90-7.10 (m, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>CN(C)C=O.[Cl-].[Na+].O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: BrCc1ccccn1
Reactant: N#Cc1ccc(O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.3 %

Procedure:
To a solution of 4-cyanophenol (5 g, 42 mmol) in N,N-dimethyl formamide (40 mL) were added potassium carbonate (17.4 g, 126 mmol) and 2-picolyl bromide hydrobromide (10.6 g, 42 mmol), and the solution was stirred at room temperature for 15 hours. The reaction solution was poured into brine, and the solution was extracted with ethyl acetate. The fractionated organic layer was dried over anhydrous magnesium sulfate, then, filtered by NH silica gel lined over a glass filter, and the filtrate was concentrated to obtain the title compound (4.7 g, 22.4 mmol, 53%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].[NH4+].[Cl-].CC[N:39](C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:39])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(N)=O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid 251 (90 mg, 0.2 mmol) was dissolved in DMF (2 mL) and treated with NH4Cl (40 mg, 0.8 mmol), DIPEA (0.3 mL, 2 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 100 mg, 0.4 mmol). The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added, and the mixture was extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated. The crude was purified by 10% MeOH/EtOAc following by trituration with minimal EtOAc to provide 74 mg (82% yield) of 196. LC/MS (ESI+): m/z 463(M+H). 1H NMR (500 MHz, DMSO) δ 8.44-8.26 (m, 2H), 8.01 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.4, 1.8, 1H), 7.35 (d, J=1.7, 1H), 7.15 (s, 1H), 6.79 (s, 1H), 5.82 (dt, J=13.3, 6.6, 1H), 4.52 (s, 4H), 2.25 (s, 3H), 1.75 (s, 6H), 1.47 (d, J=6.6, 6H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: COCCl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (3.00 g, 18.0 mmol) in 36 mL of dichloromethane was added N,N-diisopropylethylamine (9.2 mL, 54 mmol), 4-dimethylaminopyridine (0.22 g, 1.8 mmol), and chloromethyl methyl ether (2.7 mL, 36 mmol) at room temperature, successively. After being stirred at room temperature overnight, the reaction mixture was diluted with a 1:1 solution (200 mL) of ethyl acetate and hexane. The solution was washed with 1M HCl four times, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain the title compound as a white solid (3.71 g, 98%).
Reaction SMILES: [F:1][C:2]1([C:14]([O:16]C)=[O:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Cl>CC(O)=O>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C:2]([F:1])([C:14]([OH:16])=[O:15])[CH2:3]1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)C1(F)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(F)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To 1-tert-butyl 3-methyl 3-fluoropyrrolidine-1,3-dicarboxylate (100 mg) was added a mixed solution of concentrated hydrochloric acid (1 mL) and AcOH (0.2 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 1 hour, and then stirred at 100° C. for 5 hours. After confirming that the starting materials were lost, the resultant was concentrated under reduced pressure and then azeotroped with toluene three times. The residue was dissolved in a mixed liquid of acetone (0.6 mL) and water (1 mL), and Na2CO3 (64 mg) and DIBOC (132 mg) were added thereto at 0° C., followed by warming to room temperature and then stirring for 15 hours. The reaction mixture was concentrated under reduced pressure and acetone was evaporated. To the residue was added diethylether for liquid separation. The aqueous layer was combined, cooled to 0° C., and adjusted to pH=2 to 3 with 2 M hydrochloric acid. EtOAc was added thereto for extraction. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain 1-(tert-butoxycarbonyl)-3-fluoropyrrolidine-3-carboxylic acid (70 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][N+:10]([O-])=O)=[CH:4][CH:3]=1>CCO.[Pd]>[NH2:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:13]
Reactant: Cc1ccc(C(O)C[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(O)CN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 10% Pd/C (24 mg) in a solution of 1-(4-methylphenyl)-2-nitroethanol (50 mg, 0.276 mmol) in absolute EtOH (1 mL) was stirred overnight at room temperature under 15 psi of H2. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to afford 2-amino-1-(4-methylphenyl)ethanol as an oil. LCMS calc.=152.10; found=152 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.20 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.57 (dd, J=7.9, 3.9 Hz, 1H), 2.86 (dd, J=12.7, 3.9 Hz, 1H), 2.76 (dd, J=12.7, 7.9 Hz, 1H), 2.33 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16](SC)SC)[C:4]=2[CH:3]=1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[CH:3]=1
Reactant: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCCCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCC(CCCCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a solution of 2,7-dibromo-9-(bis-methylsulfanyl-methylene)fluorene (5.1 g, 12 mmol) in dry THF (100 ml) at 0° C. under nitrogen, was added a solution of lithium tetrachlorocuprate (5 ml of a 0.1 M solution in THF, 5 mol %). A solution of octylmagnesium bromide (13 ml of a 2.0M solution in diethyl ether, 0.026 mol) was added dropwise over 30 min. The reaction was stirred for 2 h at 5° C. The reaction was cooled to 0° C. and further lithium tetrachlorocuprate (1 ml of a 0.1M solution in THF, 1 mol %) was added. The reaction was then stirred for 24 h at 15° C., before quenching and workup as above. Yield (60%). Purity (HPLC>99%). 1H and 13C NMR spectra as expected. M+=560 (t).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[Mg].[CH2:6]([N:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC.C1C=CC=CC=1>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]([CH2:1][CH2:2][CH3:3])([O:20][CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCBr
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCC1(OCCO)CCN(Cc2ccccc2)CC1
Yield: 50.5 %

Procedure:
A solution of 108 g of propyl bromide in 250 ml of ether was added dropwise to a refluxing mixture of 19.2 g of magnesium in 100 ml of ether and then a solution of 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4,5] decane in 500 ml of benzene was added in increments. The ether was evaporated off and then cooled and hydrolyzed with a saturated aqueous ammonium chloride solution. The benzene phase was decanted and the aqueous phase was extracted with ether. The ether phase was washed with water until neutral, dried over sodium sulfate and the solvents removed under reduced pressure. The residue (B.p. = 129° C at 0.1mm/Hg) was rectified to obtain 28 g of 2-(1-benzyl-4-propyl-4-piperidyloxy)-ethanol as a yellowish oil. The product was dissolved in 250 ml of ether and 13 ml of a 5N hydrogen chloride solution in ether were added thereto. The product was vacuum filtered and crystallized from isopropanol and dried in vacuo to obtain 12.9 g of 2-(1-benzyl-4-propyl-4-piperidyloxy)-ethanol hydrochloride in the form of colorless crystals melting at 196° C.