Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CN(C=O)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[C:4]([Cl:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2,6-dichlorophenol (11.9 g, 49.2 mmol, H. Joyce et al., J. Amer. Chem. Soc., 39, 2644 (1917)) in DMF (100 mL) imidazole (5.0 g, 74 mmol) and tert-butyldimethylsilylchloride (8.9 g, 59 mmol) was added at room temperature and the mixture was stirred for 1 h. The mixture was poured into water (300 mL) and extracted with diethyl ether (100 mL×2) and washed with water (50 mL×2), dried over MgSO4 and concentrated in vacuo gave pale yellow oil. (15.3 g, 87%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:26]CN5CCC[C@H]5[CH2:22]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.Cl.C(OC([N:44]1[CH2:52][CH2:51][C:47]2(CNC2)[CH2:46][CH2:45]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:26]1[C:47]2([CH2:51][CH2:52][NH:44][CH2:45][CH2:46]2)[CH2:22][N:21]1[CH2:20][C:18]1[S:19][C:14]2[C:13]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[N:12][C:11]([C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[C:9]4[C:5]=3[CH:6]=[CH:7][NH:8]4)=[N:16][C:15]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Reactant: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN5CCC[C@H]5C4)cc3n2)c2cc[nH]c2c1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC5(CCNCC5)C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 2-(6-fluoro-1H-indol-4-yl)-6-[(S)-1-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno-[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of (S)-octahydro-pyrrolo[1,2-c]pyrazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (29 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[CH3:15].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:15]
Reactant: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(N)cc1C
Yield: 77.2 %

Procedure:
A mixture of 3-(2-Methyl-4-nitro-phenyl)-acrylic acid methyl ester (1.47 g, 6.64 mmol) and 5% Pd/C (0.29 g) in MeOH (100 mL) is exposed to a hydrogen atmosphere (60 psi) for 12 h. The mixture is filtered through Celite and purified by flash chromatography to yield the title compound (0.99 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1B(O)O.[I:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1>[Cu]Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:16]1[CH:17]=[C:13]([I:12])[N:14]=[CH:15]1
Reactant: Ic1c[nH]cn1
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Cu]
Solvent: CO
Product: Fc1ccc(F)c(-n2cnc(I)c2)c1
Yield: 19.7 %

Procedure:
Following a procedure similar to that outlined in Chem. Comm. 2004, 188-189: A solution of 2,5-difluorophenylboronic acid (47 mg, 0.30 mmol), 4-iodo-1H-imidazole (46 mg, 0.24 mmol), copper(I) chloride (1.8 mg, 0.018 mmol), and 1 mL of methanol was stirred under air at 60° C. for 3 h, then concentrated. Column chromatography (0-33% EtOAc/hexanes) afforded 14.5 mg (20%) of 1-(2,5-difluorophenyl)-4-iodo-1H-imidazole as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](C(O)=O)[CH:7]=[CH:6]2.[N-:16]=[N+]=[N-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH2:16])[CH:7]=[CH:6]2
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2cc(C(=O)O)ccc2c1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(N)ccc2c1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a 50 ml two-necked flask, 1.0 g (3.5 mmol) of 6-methoxynaphthalene-2-carboxylic acid (Compound 1), 2.28 g (35.0 mmol) of sodium azide and 15.0 g of polyphosphoric acid (PPA) were added, and the mixture was stirred at 40° C. for 12 hours. To the resulting mixture, 100 g of ethyl acetate was added and the obtained mixture was washed with saturated aqueous sodium hydrogen carbonate, followed by drying the product over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
Cis-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.233 g, 5.82 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.233 g, 5.82 mmol) dissolved in water (2.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.357 mL, 5.82 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.361 g, 66%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.84-2.14 (m, 4H), 2.52-2.62 (m, 1H), 2.71-2.80 (m, 1H), 2.95-3.05 (m, 1H), 3.09-3.20 (m, 1H), 3.64 (s, 3H), 3.95-4.06 (m, 1H), 4.20-4.30 (m, 1H), 5.74 (s, 1H), 6.77-6.83 (m, 1H), 6.90-6.98 (m, 1H), 6.98-7.09 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2
Reactant: O=C1CCc2cc(C#CCO)ccc21
Agent: [Pd]
Solvent: CO
Product: O=C1CCc2cc(CCCO)ccc21
Reaction time: 12 h
Yield: 94.8 %

Procedure:
To a solution of 5-(hydroxyprop-1-yn-1-yl)-2,3-dihydro-1H-indene-1-one (1.06 g, 5.71 mmol) in MeOH was added 10% Pd/C and hydrogenated by means of Pair shaker. After 12 h, the reaction mixture was filtered on Celite and concentrated in vacuo to give 5-(3-hydroxypropyl)-2,3-dihydro-1H-inden-1-one (1.03 g, 94% yield): MS (EI) for C12H14O2: 191.24 (MH+).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[CH:26]=1)([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=1)[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[F:1][C:2]([F:42])([F:43])[C:3]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:32]([O:41][S:52]([CH3:51])(=[O:54])=[O:53])([C:37]([F:38])([F:39])[F:40])[C:33]([F:36])([F:35])[F:34])[CH:26]=1)([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:15]([C:16]([F:18])([F:17])[F:19])([O:20][S:52]([CH3:51])(=[O:54])=[O:53])[C:21]([F:22])([F:23])[F:24])[CH:9]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(c2ccc(C)c(C(O)(C(F)(F)F)C(F)(F)F)c2)(C(F)(F)F)C(F)(F)F)cc1C(O)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(c2ccc(C)c(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)c2)(C(F)(F)F)C(F)(F)F)cc1C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
10.1 g (15.2 mmol) of 1,1,1,3,3,3-hexafluoro-2,2-bis-[4-methyl-3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-propane were dissolved in 50 ml of methylene chloride, and 3.4 g (33 mmol) of triethylamine were added at 0° C. 4.0 g (34.7 mmol) of methanesulfonyl chloride in 20 ml of methylene chloride were added dropwise at 0° to 5° C. The mixture was stirred for 24 hours at room temperature, separated off from the precipitated salt, washed with water, dried and evaporated down. The oily residue was recrystallized. 9.2 g of 1,1,1,3,3,3-hexafluoro-2,2-bis-[4-methyl-3-(2,2,2-trifluoro-1-methanesulfonyloxy-1-trifluoromethyl-ethyl)-phenyl]-propane were obtained (colorless crystals, m.p.: 135° C. [from toluene]).
Reaction SMILES: [CH3:1][O:2][Si:3](OC)([CH3:5])[CH3:4].C(OCC)C.[CH2:13]([Si:16]([CH2:25][CH:26]=[CH2:27])([CH2:22][CH:23]=[CH2:24])[CH2:17][CH2:18][CH2:19][Mg]Br)[CH:14]=[CH2:15].Cl>O>[CH2:13]([Si:16]([CH2:25][CH:26]=[CH2:27])([CH2:22][CH:23]=[CH2:24])[CH2:17][CH2:18][CH2:19][Si:3]([O:2][CH3:1])([CH3:5])[CH3:4])[CH:14]=[CH2:15]
Reactant: CO[Si](C)(C)OC
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Mg]Br
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C=CC[Si](CC=C)(CC=C)CCC[Si](C)(C)OC
Temperature: 0 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
Under a nitrogen atmosphere, dimethoxydimethylsilane (31) (1.0 ml, 7.0 mmol) was added to a reaction container, cooled down to 0° C., diethyl ether solution of 0.72M 3-(triallylsilyl)propylmagnesium bromide (24) (19.44 mL, 14 mmol) was added dropwise. After the dropwise adding, stirring was continued at room temperature for 5 hours. To the reaction mixture, water was added to stop the reaction, then 10% hydrochloric acid was added until the salt was completely dissolved. The obtained organic layer was separated and the obtained water layer was extracted with diethyl ether. The collected organic layer was washed each with saturated sodium bicarbonate aqueous solution and saturated saline solution in this order, dried over anhydrous magnesium sulfate, then filtered, concentrated under reduced pressure, obtaining {3-(triallylsilyl)propyl}(methoxy)dimethylsilane (32) represented by the following chemical reaction equation (yield: 1.5 g, yield (%): 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[OH:9].[OH-:10].[K+].Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:10])[C:3]=1[OH:9]
Reactant: [OH-]
Reactant: Oc1c(F)cccc1I
Agent: Cl
Agent: [K+]
Product: Oc1cccc(F)c1O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a 500 ml flask were added 119 g (0.5 mol) of 2-fluoro-6-iodophenol and 200 ml of a 30% aqueous potassium hydroxide solution and they were reacted under vigorous stirring under a reflux temperature for 8 hours. After the termination of the reaction, the mixture was cooled to ordinary temperature and neutralized with hydrochloric acid to adjust pH between 2 and 3. After filtration, the filtrate was washed with water to obtain 49.9 g of a product [H]. The process yield was 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Sc3ccc(Cl)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-chlorobenzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 251.7-253.3° C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.62 (m, 5H), 6.39 (s, 1H), 5.78 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)−79.4 (d, J=6.5 Hz). ESLRMS m/z 419 (M−H). ESHRMS m/z 418.9559 (M−H, Calc'd 418.9523). Anal. Calc'd for C17H9Cl2F3O3S: C, 48.47; H, 2.15; Cl, 16.83; S, 7.61. Found: C, 48.38; H, 2.12; Cl, 17.09; S, 7.75.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=O)[CH3:12]>>[CH3:12][C:11]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=1
Reactant: CC(=O)Nc1ccccn1
Reactant: O=[N+]([O-])c1ccccc1I
Product: Cc1nc2ccccc2n1-c1ccccn1
Yield: 38.2 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and 2-acetamido-pyridine (82 mg, 0.6 mmol) yielded the title compound as brown solid (40 mg, 38%). mp 121-123° C. 1H NMR (DMSO) δ 2.69 (s, 3H), 7.36-7.46 (m, 2H), 7.53 (d, J=7.4 Hz, 1H), 7.68 (dd, J=7.6, 4.7Hz, 1H), 7.77 (d, J=7.6Hz, 1H), 7.81 (d, J=7.9Hz, 1H), 8.21 (dd, J=7.9, 7.6Hz, 1H), 8.75 (d, J=4.7Hz); 13C NMR δ 13.6, 112.0, 116.1, 121.0, 124.7, 124.9, 133.0, 135.2, 140.1, 147.2, 150.0, 151.7, 157.9. HRMS (FAB): cal. for C13H12N3 [M+H+]: 210.1031; found: 210.1025.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH3:10])=[O:7]
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(C)c2)cc1
Yield: 43.8 %

Procedure:
The title compound (D33) (30 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D14) (50 mg, 0.18 mmol) and 3-methylbenzyl bromide (0.05 ml, 0.36 mmol). (Na2CO3: 2.5 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: C(OC([N:8]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[C:20]([C:29]([O:31][CH3:32])=[O:30])=[CH:19][C:18]2=[O:33])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:39]1[C:38]2[CH:43]=[CH:44][C:35]([CH2:34][NH:8][CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[C:20]([C:29]([O:31][CH3:32])=[O:30])=[CH:19][C:18]4=[O:33])[CH2:13][CH2:14]3)=[CH:36][C:37]=2[O:42][CH2:41][CH2:40]1
Reactant: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To 2 mL of a chloroform solution containing 0.25 g of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate, 2 mL of trifluoroacetic acid was added and stirred for 16 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 0.12 g of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([N:14]([CH2:16][C:17]([OH:19])=O)[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([N:14]([CH2:16][C:17]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24])=[O:19])[CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CN(CC(=O)O)C(=O)CCC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC(=O)N1CCC[C@H]1CO)C(=O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
N-(benzyloxysuccinyl)sarcosine (139.5 g, 0.5 mol), L-prolinol (50.5 g, 0.5 mol) and triethylamine (200 ml) are dissolved in methylene chloride (2 l), and a solution of DMC (127 g, 0.75 mol) in methylene chloride (500 ml) is added dropwise thereto under water-cooling over a period of thirty minutes. The mixture is stirred at room temperature for a further three hours, and the reaction liquid is washed successively with water (1 l), a saturated aqueous solution of sodium hydrogen carbonate (1 l), 1N hydrochloric acid (1 l) and water (1 l). The organic layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is then concentrated to dryness under reduced pressure, and the residue is purified by column chromatography on silica gel (chloroform:methanol) to give N-(benzyloxysuccinyl)sarcosyl-L-prolinol (88.4 g, 48.8%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([N:21](CC)CC)C.C(Cl)(=O)OCC>C1COCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:21])=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(C(N)=O)cc1)OCC

Procedure:
To a solution of 1.36 g of 4-diethoxyphosphinylmethylbenzoic acid and 0.56 g of triethylamine in 15 ml of dry THF was slowly added a solution of 0.60 g of ethyl chlorocarbonate in 2 ml of dry THF under ice-cooling with stirring. After stirring for 30 minutes under ice-cooling, ammonia gas was slowly bubbled into the mixture for 15 minutes, stirred for 2 hours at room temperature. After adding 30 ml of water, the reaction mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; chloroform:methanol=10:1) to give 4-diethoxyphosphinylmethylbenzamide. it was recrystallized from chloroform-benzene mixture to give 0.80 g of colorless plate crystals. mp: 177.0°-177.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH2:16][C:17]#[N:18])[CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[N:21]=2)=[CH:4][CH:3]=1.C(O)C.[H][H]>O=[Pt]=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][NH2:18])[CH:13]=[CH:12][N:11]3[C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[N:21]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3cc(CC#N)ccn23)n1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3cc(CCN)ccn23)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 300 mL pressure bottle containing nitrile 22 (980 mg, 2.41 mmol) was charged with ethanol (18 mL), chloroform (2 mL), and then PtO2 (200 mg, 0.881 mmol). The pressure bottle was then sealed, then charged with 50 psi hydrogen, and the reaction mixture was allowed to stir at room temperature for 12 hours, after which additional PtO2 (500 mg, 1.14 mmol) was added, and an the pressure bottle was charged with an additional 50 psi hydrogen then sealed, and the reaction mixture was stirred at room temperature for 3 hours. At this point, TLC analysis showed the reaction to be complete. The reaction mixture was then filtered through successive 0.45 □m Gelman nylon acrodiscs. The filtrate was then concentrated under reduced pressure and carried onto the next step without further purification. Crude yield of 23: 1.20 g (121%). MS (ESI+) 412.2.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([CH2:19][OH:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][S:15][C:11]=3[C:10]=2[F:21])[CH2:3]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([CH:19]=[O:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][S:15][C:11]=3[C:10]=2[F:21])[CH2:3]1
Reactant: Cc1nsc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nsc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of {6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-methyl-1,2-benzothiazol-5-yl}methanol (Intermediate 157, 0.18 g, 0.6 mmol) in DCM/CH3CN mixture (3 mL, 1:1 v/v) was added NMO (0.12 g, 0.7 mmol) followed TPAP (0.04, 0.2 mmol) and mixture stirred for 2 h at room temperature. The reaction mixture filtered through silica gel bed and washed with EtOAc. The organic phase concentrated under reduced pressure to give title compound as a yellow crystalline solid. Yield: 0.12 g (67%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1)([CH3:3])=[CH2:2].CN1C=CN=C1.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C1(C)C=CC=CC=1>[CH3:3][C:1]1([C:4]2[CH:9]=[N:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=2)[CH2:2][CH:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: C=C(C)c1ccc(C(F)(F)F)nc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1(C)c1ccc(C(F)(F)F)nc1
Yield: 62.9 %

Procedure:
A toluene (2 ml) solution of 5-isopropenyl-2-(trifluoromethyl)pyridine (219 mg, 1.17 mmol), Co(TPP) (26 mg, 0.039 mmol) and 1-methyl-1H-imidazole (320 mg, 3.9 mmol), ethyl diazoacetate (208 mg, 1.8 mmol) were treated in the same procedure as described in Example 2H. The crude residue (201 mg, 63% yield of the title compound as a black oil) was used in a further reaction without purification.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.Cl>>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Product: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CN)c1
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate (130 mg, 0.232 mmol) was treated with HCl (0.581 mL, 2.32 mmol), After stirring for 3 hours, the material was concentrated to yield 100 mg of methyl 2-(3-(aminomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate.