Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([F:27])[CH:24]=[C:25]([F:26])[C:20]=2[O:19][CH2:18][C:17]1=[O:28].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[CH:22]=[C:23]([F:27])[CH:24]=[C:25]([F:26])[C:20]=4[O:19][CH2:18][C:17]3=[O:28])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: O=C1COc2c(F)cc(F)cc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)cc(F)cc2N1CCCN1CCC(OCC2CC2)CC1
Yield: 50.4 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.076 g, 0.49 mmol), 4-(3-chloropropyl)-6,8-difluoro-4H-benzo[1,4]oxazin-3-one (0.143 g, 0.55 mmol), K2CO3 (0.136 g, 0.98 mmol) and KI (0.147 g, 0.98 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; heptanes/EtOAc 1:1) to give the title compound (0.094 g, 50%). 1H NMR (CDCl3) δ 6.83-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.60 (s, 1H), 3.92 (t, J=6.8 Hz, 2H), 3.36-3.24 (m, 3H), 2.77-2.68 (m, 2H), 2.34 (t, J=6.8 Hz, 2H), 2.09 (t, J=9.6 Hz, 2H), 1.93-1.76 (m, 4H), 1.66-1.56 (m, 2H), 1.08-0.97 (m, 1H), 0.53-0.48 (m, 2H), 0.19-0.15 (m, 2H); 13C NMR (CDCl3) δ 163.9, 157.4 (dd, J=241.4 Hz, J=12.7 Hz), 151.4 (dd, J=247.6 Hz, J=14.3 Hz), 131.4 (dd, J=12.5 Hz, J=4.7 Hz), 130.2 (dd, J=14.6 Hz, J=3.9 Hz), 99.3 (dd, J=26.9 Hz, J=22.3 Hz), 98.6 (dd, J=28.4 Hz, J=3.5 Hz), 74.8, 72.8, 67.8, 55.1, 51.5, 40.3, 31.5, 24.8, 11.1, 3.2.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[C:22]2[N:21]=1.B(F)(F)F.O>C(#N)C>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:9]1[S:14][CH2:15][C:6]([CH2:5][S:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]3[N:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[C:22]3[N:21]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: Cc1cc(S)nc2c(C(=O)O)cnn12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: O
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)nc2c(C(=O)O)cnn12
Reaction time: 1.5 h

Procedure:
A suspension of 4.00 g of (7R)-7-aminocephalosporanic acid and 3.34 g of 5-mercapto-7-methylpyrazolo[1,5-a]-pyrimidine-3-carboxylic acid in 20 ml of acetonitrile was treated with 25 ml of a 20 percent solution of boron trifluoride in acetonitrile and the mixture was stirred at 20° for 1.5 hours. 150 ml of cold water were added and the mixture was stirred at 0° for 1.5 hours. The precipitate was filtered off under suction and dried. There was obtained (6R,7R)-7-amino-3-[[(3-carboxy-7-methylpyrazolo-[1,5-a]pyri-midine-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid as an almost colorless powder.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])=[CH:7][CH:6]=1)(=O)C.C[O-].[Na+].Cl>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH:13]([NH:15][C:16](=[O:18])[CH3:17])[CH3:14])=[CH:9][CH:10]=1
Reactant: CC(=O)NC(C)CCc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC(C)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(3-Acetylaminobutyl)phenyl acetate (1.06 g, 4.25 mmol) was dissolved in 10 ml of methanol and, after addition of sodium methoxide (689.3 mg, 12.76 mmol), the reaction mixture was stirred at RT for 2 h. The pH was adjusted to 7 by adding dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated in vacuo. Yield: 805 mg (91%), M+H+: 208.15.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([Mg]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccccn1
Reactant: Cl[Mg]c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2ccccn2)cc1
Temperature: 50 °C
Yield: 97.9 %

Procedure:
216.5 g (3.0 mol) of tetrahydrofuran (THF), 113.5 g (1.0 mol) of 2-chloropyridine and 0.24 g of Pd(dppf)Cl2 (0.03 mol %) are placed in a flask and heated to 50° C. while stirring. 510 g of phenylmagnesium chloride solution in THF (27% strength) are slowly metered in while cooling externally so that the temperature does not exceed 50° C. The mixture is then stirred for another 90 minutes at this temperature. It is slowly hydrolyzed with 250 g of water and allowed to cool to room temperature. After phase separation, the aqueous phase is stirred with 250 ml of tert-butyl methyl ether. After renewed phase separation, the organic phases combined and the reaction mixture is evaporated at 150 mbar. It is subsequently distilled at atmospheric pressure until a bottom temperature of 80° C. has been reached. The distillation residue is distilled at 10 mbar, giving 152.0 g of 2-phenylpyridine (98.1%), purity: 98.7% (according to GC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N+:12]([O-])=O)[C:4]=1[CH3:15].[N-:16]=[N+:17]=[N-].[Na+]>CS(C)=O>[N:12]([C:5]1[C:4]([CH3:15])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])=[N+:16]=[N-:17]
Reactant: COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(N=[N+]=[N-])c1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-methoxy-2-methyl-3,4-dinitrobenzene (3.4 g, 16 mmol) in 60 mL of DMSO was added NaN3 (2.1 g, 32 mmol) at one portion and the reaction was stirred for 72 hours at room temperature. Then the reaction was poured into 500 mL of ice water, and then was extracted with DCM (100 mL×3). The combined organic layers were washed with water, dried and concentrated to about 100 mL of solvent. Then 100 mL of toluene was added and the residual DCM was removed under reduced pressure, the toluene solution of 2-azido-4-methoxy-3-methyl-1-nitrobenzene was used directly the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[ClH:25]>C(O)C>[ClH:25].[ClH:25].[NH2:17][CH:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][N:2]([CH3:1])[CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:16][CH2:15]1
Reactant: CN(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C1CCOCC1
Agent: Cl
Solvent: CCO
Product: CN(CCN1CCC(N)CC1)C1CCOCC1
Reaction time: 7 h

Procedure:
Into a solution of tert-butyl 1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]-4-piperidinylcarbamate (2.72 g) in ethanol (30 ml) was added concentrated hydrochloric acid (10 ml), and the resulting mixture was stirred for 7 hours. After the reaction mixture was concentrated under reduced pressure, ethanol and methanol are added to the residue, and the resulting mixture was concentrated further. The precipitate was collected by filtration and was washed with ethanol and methanol to obtain 4-amino-1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidine dihydrochloride (1.65 g) as a light yellow powder.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13](=O)([O-])[O-].[Na+].[Na+].IC>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
4-Fluoro-2-methyl-5-nitro-phenol (1.08 g, 6.3 mmol) was dissolved in acetone (100 ml). To this was added solid sodium carbonate (2 eq, 1.34 g) and iodomethane (10 eq, 3.75 ml). The mixture was allowed to stir at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give 1-fluoro-4-methoxy-5-methyl-2-nitro-benzene (1.18 g, quantitative) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[B:13](OCCO)([OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([B:13]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[OH:21])[CH:19]=[CH:18][CH:17]=1
Reactant: OCCOB(O)c1cccc(Cl)c1
Reactant: COc1ccc([Mg]Br)cc1OC
Product: COc1ccc(B(O)c2cccc(Cl)c2)cc1OC

Procedure:
(3-Chlorophenyl)(3,4-dimethoxyphenyl)borinic acid was prepared from 3,4-dimethoxyphenylmagnesium bromide and 3-chlorophenylboronic acid ethylene glycol ester by the procedure described in Example 6a. The title complex product was made by the methodology described in Section 5.3.7.1, and obtained as yellow crystals. MS (ESI, positive): m/z=404 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ 9.17 (d, 1H), 8.78 (d, 1H), 7.90 (dd, 1H), 7.70 (t, 1H), 7.43 (d, 1H), 7.30-7.17 (m, 5H), 6.89-6.80 (m, 3H), 3,66 (s, 3H) and 3.62 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=1)[C:9]([OH:11])=O)[CH2:4][CH3:5])[CH3:2].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:22]([NH:24]O)=[NH:23])[CH3:18]>>[CH2:17]([C:19]1[CH:20]=[C:21]([C:22]2[N:24]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:7]=3)[O:11][N:23]=2)[CH:26]=[C:27]([CH3:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[CH3:18]
Reactant: CCc1cc(C(=N)NO)cc(C)c1NS(C)(=O)=O
Reactant: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1NS(C)(=O)=O
Yield: 36.6 %

Procedure:
The title compound (24 mg) is prepared in analogy to Example 11 starting from 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid (32 mg, 143 μmol) and 3-ethyl-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine (40 mg, 150 mmol); LC-MS**: tR=0.91 min, [M+H]+=459.09; 1H NMR (CDCl3): δ0.85 (t, J=7.3 Hz, 6H), 1.36 (t, J=7.3 Hz, 3H), 1.69-1.89 (m, 4H), 2.56 (s, 3H), 2.57-2.65 (m, 1H), 2.93 (q, J=7.5 Hz, 2H), 3.18 (s, 3H), 4.02 (s, 3H), 5.92 (s, 1H), 7.33 (s, 1H), 7.44 (s, 1H), 7.97 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>[Pd].C1(C)C(C)=CC=CC=1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:12]3[C:17]([C:6]=2[CH:5]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C1CCCCC1
Reactant: COc1ccc(NN)cc1
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccccc1C
Product: COc1ccc2[nH]c3ccccc3c2c1
Yield: 74 %

Procedure:
Bis-1,3(N-3'-methoxycarbazolyl)propane. Reaction of p-methoxyphenylhydrazine hydrochloride with cyclohexanone (exothermic) was carried out as for the methyl substituted compound (See Liebigs Ann. der Chemie, 359, 52, 1908) in 82% yield, mp 105°-7.5° C. This compound was dehydrogenated with 10% palladium on charcoal in xylene, as above, to give 74% of 3-methoxycarbazole, recrystallized from benzene/heptane, mp 148.5°-9.5° C (lit. mp 150.5°-1.0° C).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C([O-])([O-])=[O:34].[K+].[K+].FC(F)CI>CC#N>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:34])=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: O=C([O-])[O-]
Agent: FC(F)CI
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To a solution of compound 9 (100 mg, 0.27 mmol) in CH3CN (5 mL) was added K2CO3 (74 mg, 0.54 mmol). After addition, the resulting mixture was stirred at room temperature for 10 min. Then 1,1-difluoro-2-iodo-ethane (51.8 mg, 0.27 mmol) in CH3CN (5 mL) was added dropwise via a syringe with stirring. The mixture was stirred at 60° C. overnight. Then the mixture was filtered off, the filtrate was concentrated to give compound 10 (90 mg, 77%) as a white solid, which was used for the next step directly without purification. LC-MS tR=1.337 min in 2 min chromatography, MS (ESI) m/z 435.2 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:16]=3[N:15]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[F:23][C:22]1[C:16]2[N:15]=[C:14]([CH2:13][CH2:12][N:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[NH:18][C:17]=2[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCN(CCc2nc3c(F)cccc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(CCc2nc3c(F)cccc3[nH]2)CC1
Yield: 54.5 %

Procedure:
A solution of (b) (2.0 g, 6.3 mmol), 1M aqueous sodium hydroxide solution (1.2 ml, 1.2 mmol) in ethanol (40 ml) was stirred at room temperature for 3 hours. After concentration, the residue was diluted with water and acidified with a saturated solution of potassium hydrogenosulfate to pH 5. The precipitated solid was filtered, washed with water and dried under vacuum to afford a foam (1.0 g, 54%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:29])=[C:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[C:13](=[O:20])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].Cl[CH:32]([F:34])[F:33]>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:29])=[C:12]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=1)[C:13]([O:20][CH:32]([F:34])[F:33])=[N:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Reactant: FC(F)Cl
Product: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [3-(4-bromobenzyl)-8-chloro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid tert-butyl ester and chlorodifluoromethane.
Reaction SMILES: Cl.Cl.[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:38][C:39]1[NH:43][N:42]=[C:41]([CH2:44][C:45](O)=[O:46])[N:40]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][N:20]([C:45](=[O:46])[CH2:44][C:41]4[N:40]=[C:39]([CH3:38])[NH:43][N:42]=4)[C@@H:19]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc(N2CCN[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c(C)n3)[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of (S)-1-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-(pyrrolidin-1-ylmethyl)piperazine, dihydrochloride (Example 40, Compound 128) (173 mg, 0.40 mmol) in CH2Cl2 (1 mL) and DMF (1 mL) was treated with diisopropylethylamine (348 uL, 2.0 mmol), 2-(5-methyl-1H-1,2,4-triazol-3-yl)acetic acid CAS [720706-28-5] (68 mg, 0.48 mmol) followed by HBTU (162 mg, 0.48 mmol). The reaction mixture was stirred for 16 h after which time the mixture was partitioned between CH2Cl2 (3 mL) and a saturated aqueous solution of NaHCO3 (2 mL). The organic portion was further washed with NaHCO3 (2×3 mL) followed by brine (3 mL). The organic portion was then dried over MgSO4, filtered, and evaporated to afford quenched with evaporated and the residue purified by silica gel flash chromatography with 5% MeOH/EtOAc the 10% MeOH/EtOAc containing 1% NH4OH as eluant to afford product as a foam (123 mg, 64%). LC/MS (Method B) 2.18 min, [M+1]+ 483. Potency class C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18]/[C:17](=[N:21]\[C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)/[NH:16]3)[C:14]3[CH:13]=[C:12]([Cl:30])[N:11]=[C:10]([F:31])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[NH2:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][N:34]=1.C(P(C(C)(C)C)C1(CCC)CC(CCC)=CC(CCC)=C1C1C=CC=CC=1)(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:30][C:12]1[N:11]=[C:10]([F:31])[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:20][CH2:19][O:18]/[C:17](=[N:21]\[C:22](=[O:29])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)/[NH:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([NH:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][N:34]=1)=[CH:7][CH:6]=3
Reactant: Cc1cccnc1N
Reactant: O=C(/N=C1/N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F)c1ccccc1
Agent: [Pd]
Agent: CCCC1=CC(CCC)=C(c2ccccc2)C(CCC)(P(C(C)(C)C)C(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccnc1Nc1ccc2c(c1)[C@@]1(CCO/C(=N\C(=O)c3ccccc3)N1)c1cc(Cl)nc(F)c1O2
Temperature: 100 °C
Yield: 26.2 %

Procedure:
A mixture of (S,Z)—N-(7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazinan]-2′-ylidene)benzamide (0.25 g, 0.497 mmol), 2-amino-3-picoline (0.055 ml, 0.547 mmol), pd2(dba)3 (0.023 g, 0.025 mmol) and 2-di-t-butylphosphino-2,4,6-tri-1-propyl-1,1-biphenyl (0.037 g, 0.087 mmol) was purged with N2 followed by the addition of toluene (2 mL) and lithium bis(trimethylsilyl)amide (1.243 ml, 1.243 mmol). The resulting mixture was heated at 100° C. and after 30 min the reaction was cooled, diluted with EtOAc and washed with saturated NH4Cl. The organic phase was dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-100% EtOAc/hexanes. The product was repurified by HPLC to afford (S,Z)—N-(3-chloro-1-fluoro-7-((3-methylpyridin-2-yl)amino)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazinan]-2′-ylidene)benzamide (0.069 g, 0.130 mmol, 26% yield).
Reaction SMILES: C([O:8][C:9](=[O:45])[C@H:10]([CH2:24][O:25][C@H:26]1[O:43][C@@H:42]([CH3:44])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@@H:27]1[O:28][C:29](=[O:31])[CH3:30])[N:11](OC(=O)C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:29]([O:28][C@H:27]1[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:42]([CH3:44])[O:43][C@@H:26]1[O:25][CH2:24][C@@H:10]([C:9]([OH:45])=[O:8])[NH2:11])(=[O:31])[CH3:30]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC[C@@H](C(=O)OCc2ccccc2)N(OC(=O)c2ccccc2)C(=O)O)O[C@@H](C)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC[C@H](N)C(=O)O)O[C@@H](C)[C@H]1OC(C)=O
Reaction time: 16 h
Yield: 81.3 %

Procedure:
A solution of N-Carboxybenzoyloxy-3-O-(2,3,4-tri-O-acetyl-β-L-fucopyranosyl)-L-serine Benzyl Ester (600 mg, 1.0 mmol) in 98% ethanol (15 ml) containing 5% Pd/C (300 mg) was hydrogenated for 16 h at room temperature and at 1 atmospheric pressure. The catalyst was collected on celite and washed with several portions of 98% ethanol. The filtrate and washings were combined and concentrated to dryness to give 3-O-(2,3,4-tri-O-acetyl-β-L-fucopyranosyl)-L-serine (306.6 mg, 81.6%) as a white powder Rf =0.34 (dichloromethane:methanol:water, 60:35:3). 1H-NMR (CD3OD): ε 5.23 (dd, 1 H, J3,4 =3.0, J4,5 =1.0 Hz, H-4), 5.14-5.02 (m, 2 H, H-2 and 3), 4.68 (d, 1 H, J1,2 =7.5 Hz, H-1), 4.24 (dd, 1 H, Jgem =7.5 Hz, H-1), 4.24 (dd, 1 H, Jgem =10.5, JCH,CHN =2.0 Hz, serine CH), 4.13-4.04 (m, 2 H, serine CHH and CHN), 4.01 (dq, J5,6 =6.5 Hz, H-5), 2.13, 2.05 and 1.93 (each s, 3 H, Ac), 1.19 (d, 3 H, H-6). N-(9-Fluorenylmethyloxycarbonyl)-3-O-(2,3,4-tri-O-acetyl-β-L-fucopyranosyl)-L-serine (FIG. 1E).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20](=[NH:21])[NH:35][OH:36])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C(=N)NO)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-[5-Cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (0.5 g, 1.04 mmol) was dissolved in the mixture ethanol/water (30 mL/14 mL) and heated to 80° C. Hydroxylamine hydrochloride (7.22 g, 104 mmol) and potassium carbonate (14.5 g, 105 mmol) were slowly added and the mixture kept stirring at 80° C. for 1 h. The crude was filtered and the retrieved solid was thoroughly washed with acetonitrile. The filtrate was concentrated under reduced pressure, yielding a yellow solid residue, which was purified by HPLC to afford Compound A99 (0.51 g, 78%). Exact mass calculated for C21H27FN6O6S 510.17, found 511.2 (MH+).
Reaction SMILES: [S:1]1(=O)(=O)[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C.Cl>[S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=S1(=O)CCc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: c1ccc2c(c1)CCS2
Temperature: 0 °C
Yield: 45.9 %

Procedure:
A suspension of 2,3-dihydro-benzo[b]thiophene 1,1-dioxide (5.06 g, 30.08 mmol) in diethyl ether (150 mL) was added to a suspension of lithium aluminum hydride (10.27 g, 270.27 mmol) in diethyl ether (150 mL) at 25° C. After this time it was heated to reflux for 4 h (caution: if heating is too rapid it can exotherm rapidly and cause loss of material through the reflux condenser). It was then cooled to 0° C. in an ice bath and water (50 mL) was added very slowly. The resulting material was dissolved in 4 M aqueous hydrochloric acid (1 L). The aqueous layer was then extracted with diethyl ether (3×200 mL). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. The material was purified by passing it through a plug of silica gel using pentane as the solvent to afford 2,3-dihydro-benzo[b]thiophene (1.88 g, 46%) as a clear colorless oil.