Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([CH3:12])[C:10]=1[OH:11])=[O:5])[CH3:2].[CH2:14]([Cl:17])[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>>[C:4]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([CH3:12])[C:10]=1[O:11][CH2:15][CH2:14][Cl:17])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1[nH]c(C)c(C)c1OCCCl
Yield: 40.7 %

Procedure:
Using the method described in Example X, 18.3 g of 3-hydroxy-4,5-dimethyl-pyrrole-2-carboxylic acid ethyl ester, 20.5 g of 1,2-bromochloroethane and 18 g of anhydrous potassium carbonate give 10 g of 1-(2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy)-2-chloroethane, of melting point 81°-83° C.
Reaction SMILES: [CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[O:17][CH2:18][C:19](O)=[O:20])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:25])[N:4]1[CH3:26])[CH3:2].[C:27]([NH:34][CH2:35][CH2:36][NH2:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[CH:1](=[C:3]1[C:7]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[O:17][CH2:18][C:19]([NH:37][CH2:36][CH2:35][NH:34][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:20])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([CH3:25])[N:4]1[CH3:26])[CH3:2]
Reactant: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(OCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC=C1N(C)C(C)CC1(c1ccccc1)c1cccc(OCC(=O)NCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Product of Step 11 (0.11 g) was dissolved in acetonitrile (10 mL). To this, N-boc-ethylene diamine (0.1 g), HBTU (0.4 g), HOBT (0.15 g), and DIPEA (1 mL) were added. The reaction mixture was stirred at 25° C. for 1 hr and was evaporated under vacuum. Residue was dissolved in dichloromethane (300 mL) and was extracted with water (twice at 200 mL each). The organic layer was dried on anhydrous magnesium sulfate and was filtered and was evaporated. Crude product was loaded on a SNAP cartridge containing 100 g silica gel and eluted with a gradient of chloroform and methanol using the BIOTAGE® AB ISOLERA™ flash chromatography system. Fractions containing product were pooled and evaporated under vacuum to obtain Step 12 (0.13 g). 1H NMR (CDCl3): 1.25 δ (—CH—CH3 of isopropyl), 1.5 δ (9H, —(CH3)3 of N-boc) 1.8 δ (3H, ═CH—CH3 of ethylidene) 2.9 δ (3H, —N—(CH3)), 2.2, 2.3, 3.1 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 3.3, 3.5 δ (2H, 2H, —N—CH2-CH2-N—), 4.4 δ (1H, ═CH—CH3 of ethylidene), 4.5 (2H, —O—CH2-C(O)—), 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=494 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:35][C:36]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH:41]=[C:40]([Cl:50])[C:37]=1[CH:38]=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:38]/[C:37]2[C:36]([Cl:35])=[CH:43][C:42]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[CH:41][C:40]=2[Cl:50])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=Cc1c(Cl)cc(N2CCOCC2)cc1Cl
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2c(Cl)cc(N3CCOCC3)cc2Cl)c([N+](=O)[O-])c1
Temperature: 95 °C

Procedure:
A mixture of 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.01 g, 3.68 mmol) (from Example 3-8) and triphenylphosphine (1.06 g, 4.05 mmol) in DMF (20 mL) under N2 was heated at 95° C. Upon disappearance of the starting ester by TLC, 2,6-dichloro-4-morpholin-4-yl-benzaldehyde (1.15 g, 4.42 mmol) was added followed by K2CO3 (1.02 g, 7.36 mmol). The mixture was heated at 95° C. for 22.5 h then was allowed to cool to ambient temperature. The mixture was partitioned between EtOAc/DCM (700 mL) and Water (200 mL). The resulting orange precipitate was filtered and the organic phase was dried over Na2SO4 and concentrate under reduced pressure. The residue was triturated with EtOAc/Et2O to yield additional orange solid. The combined orange solids provided 4-[(E)-2-(2,6-dichloro-4-morpholin-4-yl-phenyl)-vinyl]-3-nitrobenzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J=1.77 Hz, 1H), 8.24 (dd, J=8.27, 1.71 Hz, 1H), 8.11 (d, J=8.21 Hz, 1H), 7.49 (d, J=16.42 Hz, 1H), 7.33 (d, J=16.42 Hz, 1H), 7.10 (s, 2H), 3.91 (s, 3H), 3.67-3.73 (m, 4H), 3.22-3.27 (m, 4H). MS (m/z) 437.1 (M+1).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)#[N:15]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[CH:24][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1)=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 4-cyanobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.32-1.45 (m, 2 H) 1.60-1.68 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 4.06-4.12 (m, 2 H) 6.67 (s, 1 H) 7.90 (d, 2 H) 8.10 (d, 2 H); MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O)(C)C>O>[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=3)[N:3]=2)[CH2:26][CH2:27]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Solvent: CC(C)O
Solvent: O
Product: N#Cc1ccc2nc(N3CCOCC3)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 79.8 %

Procedure:
A mixture comprising 338 mg of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline, 435 mg of morpholine and 20 ml of isopropyl alcohol was heated under reflux for 3 hours, followed by the addition of 30 ml of water under heating. The precipitate thus formed was recovered by filtration and washed with 30 ml of water and 30 ml of ethyl acetate. Thus, 310 mg of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23](O)=[O:24])[CH:21]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:33]>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([NH2:33])=[O:24])[CH:21]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Yield: 75 %

Procedure:
Following the procedure of Example 144, 2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetic acid and ammonium chloride were reacted to give 60 mg (75%) of 2-(4-(3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetamide. ESI MS m/z 422.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:16])[C:7]2=[O:15].O[C:18]1C=CC([N+]([O-])=O)=C2C=1CN(C)C2=O>>[CH2:1]([O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:16])[C:7]2=[O:15])[CH3:18]
Reactant: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Reactant: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Product: CCOc1ccc([N+](=O)[O-])c2c1CN(C)C2=O

Procedure:
The title compound was prepare according to the procedure for 4-Methoxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 205B) using 4-Hydroxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one and iodoethane (Compound 205C, 28.8 uL, 0.360 mmol). 1H NMR (400 MHz, CD3OD) δ=1.47 (t, J=7.1 Hz, 3 H), 3.17 (s, 3 H), 4.27 (q, J=6.9 Hz, 2 H), 4.43 (s, 2 H), 7.23 (d, J=8.8 Hz, 1 H), 7.90 (d, J=8.8 Hz, 1H). MS (ES+): m/z 251.21 (100) [MH+]; HPLC: tR=1.06 min (UPLC, Analytical).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH3:15][C:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(OCC)(=O)C>[CH3:25][C:16]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:15])[CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH2:23][CH2:24]1
Reactant: CC(C)(CCN1CCNCC1)c1ccccc1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CCN1CCN(C(=O)C2CSC(c3cccnc3)N2)CC1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 2-(3-pyridyl)thiazolidin-4-carboxylic acid (0.81 g), 1-(3-methyl-3-phenylbutyl)-piperazine (0.73 g), 1-hydroxybenzotriazole (0.50 g) and dicyclohexylcarbodiimide (0.76 g) in N,N-dimethylformamide (7 ml) was stirred under room temperature for 12 hours. To the reaction solution was added ethyl acetate (10 ml) and the insoluble matter was filtered off. To the filtrate was added 0.5N sodium hydroxide and the solution was extracted with ethyl acetate. The ethyl acetate layer was extracted with 1N hydrochloric acid. The aqueous layer was made basic with potassium carbonate and extracted with ethyl acetate. The resultant ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and elution with an ethyl acetate-methanol (10:1) mixture gave 1.32 g of 1-(3-methyl-3-phenylbutyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[N+:10]([CH:13]([CH:16]=O)[CH:14]=[O:15])([O-:12])=[O:11]>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:16]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: COc1cccc(NC=C(C=O)[N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To the HCl salt of 3-methoxy-phenylamine (4.6 g, 28.9 mmol) in 1N HCl (300 mL) was added a solution of 2-nitro-malonaldehyde (2.7 g, 19.3 mmol) in 150 mL water. After 30 min, the precipitate was filtered and rinsed with 0.1 N HCl. Air-drying in a Büchner funnel for 18 h gave 3.36 g (78%) of a light yellow/green powder. LC/MS (m/z): 245.1 (MH++Na), Rt 2.21 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])C=O.[CH:18]([O:23][CH3:24])([O:21][CH3:22])OC.[Cl-].[NH4+]>CO>[CH3:24][O:23][CH:18]([O:21][CH3:22])[C:4]1[CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(OC)OC
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: C#CCOc1cc(C(OC)OC)cc(Cl)c1OCC#C
Temperature: 0 °C
Yield: 79.3 %

Procedure:
A solution of 3-chloro-4,5-dipropargyloxybenzaldehyde (1.0 g), trimethyl orthoformate (4.0 g) and ammonium chloride (0.05 g) in methanol (20 ml) was stirred under reflux for 3 hours, and the resultant solution was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to alumina chromatography using toluene as an eluent to give 3-chloro-4,5-dipropargyloxybenzaldehyde dimetylacetal (0.94 g). nD21.0 1.5344.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH3:19][N:20]=[C:21]=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:5]=1[S:14]([NH:17][C:21]([NH:20][CH3:19])=[O:22])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(OC(F)F)ccc1OC(F)F
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NS(=O)(=O)c1cc(OC(F)F)ccc1OC(F)F
Temperature: 25 °C

Procedure:
14.5 g of 2.5-bis(difluoromethoxy)phenylsulfonamide are suspended in 50 ml of absolute methylene chloride. Then 3.5 g of methyl isocyanate are added and 6.3 g of triethylamine are subsequently added dropwise over 10 minutes to form a clear solution. The solution is stirred at room temperature for a further hour, evaporated to dryness, and the residue is dissolved in 5% sodium carbonate solution. N-[2,5-bis(difluoromethoxy)phenylsulfonyl]-N'-methylurea with a melting point of 162°-165° C., is precipitated from the solution by acidification with 10% hydrochloric acid. Yield: 15.0 g.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:9][C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1>C(Cl)Cl.CCOCC>[C:1]([C:12]1[CH:11]=[C:10]([CH3:9])[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]=1[OH:19])(=[O:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1cc(C)cc(C(=O)O)c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Acetyl chloride (14.7 ml, 5 eq.) is added slowly to an ice cooled suspension of AlCl3 (27.7 g, 5 eq.) in dry CH2Cl2 (125 ml). The reaction is stirred until most of the solid is dissolved, then 5-methyl salicylic acid 236 (6.31 g, 41 mmol) is added. The reaction is stirred at 0° C. for 1.5 hr, then at room temperature for 1.5 hr. The reaction is poured onto ice, diluted with Et2O, and washed with water, brine, dried (MgSO4). Concentration in vacuo afforded a slowly crystallizing oil. Recrystallization (CH2Cl2/hexanes) yielded pure 3-Acetyl-5-methyl salicylic acid (Example 529, Table IIIa) as 3.29 g of off white powder (41% recrystallized yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[CH2:8]([N:1]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 93.1 g (1 mole) of aniline, 342.1 g (2 mole) of benzyl bromide, and 252 g (3 mole) of sodium bicarbonate in dimethylsulfoxide is heated at 90° C. for three hours. After cooling to room temperature, the reaction mixture is poured into a four-fold excess of water, and the aqueous solution is extracted with methylene chloride. The combined organics are filtered through cotton and evaporated to yield N,N-dibenzylaniline, which is purified by flash chromatography.
Reaction SMILES: [CH3:1]N(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:1])=[C:9]([O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH:8]=1
Reactant: Oc1ccc(Br)cc1OC1CCC1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(Br)cc1OC1CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To 60 ml of N,N-dimethylformamide solution containing 6.22 g (25.6 mmol) of 4-bromo-2-cyclobutoxyphenol obtained in Reference Example 5-(d) were successively added 3.54 g of potassium carbonate and 3.2 ml of methyl iodide, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene), and the obtained crude solid was recrystallized from hexane to obtain 3.90 g of the title compound as a colorless solid. (Yield: 59%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10](=[O:11])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccc(Cl)cc1C
Reactant: Cc1ccccn1
Product: Cc1cc(Cl)ccc1[C@H](CC(=O)Cc1ccccn1)c1ccc(Br)cc1

Procedure:
In analogy to example 261, step 1, from (R)-3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-N-methoxy-N-methyl-propionamide and 2-methyl-pyridine was prepared the title compound as a yellow oil, MS (ESI+): m/z=430.0 ([M+H]+, 1Br).
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][C@H:11]([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[C:5]([O:10][C@H:11]([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](Oc1ncccc1[N+](=O)[O-])C(=O)NCC(F)(F)F
Solvent: CO
Product: C[C@@H](Oc1ncccc1N)C(=O)NCC(F)(F)F

Procedure:
To 500 mg (1.7 mmol) (2R)-2-[(3-nitro-2-pyridyl)oxy]-N-(2,2,2-trifluoroethyl)propanamide 100 mg Raney-Nickel and MeOH are added and the mixture is hydrogenated in a Parr apparatus (RT; 3 bar; over night). The catalyst is filtered off and the solvent is evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1.CCOC(C)=O.C(Cl)(=O)C>[C:24]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2F)ccn1
Reaction time: 0.75 h
Yield: 132.6 %

Procedure:
A tert-butyl 4-(2-aminopyridin-4-yloxy)-3-fluorophenylcarbamate (150 mg, 0.47 mmol) in anhydrous pyridine (0.5 mL) was cooled to 10° C. and treated with acetyl chloride (33 μL, 0.47 nmol) and the mixture stirred for 45 min. An additional portion of acetyl chloride (16 μL, 0.24 mmol) was added to the reaction and stirring continued for 25 min. The mixture was diluted with EtOAc (20 mL), washed with brine, dried (MgSO4) and concentrated under vacuum to give the title compound (115 mg, 68%). 1H NMR (DMSO-d6) δ 10.55 (s, 1H), 9.71 (s, 1H), 8.16 (d, 1H, J=5.5 Hz), 7.63-7.55 (m, 2H), 7.29-7.23 (m, 2H), 6.68-6.63 (m, 1H), 2.02 (s, 3H), 1.48 (s, 9H); MS(ESI+): m/z 362.22 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:9])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[Na+:10].[NH4+:11]>>[NH2:11][CH2:2][CH:3]([OH:9])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[Na+:10]
Reactant: O=S(=O)([O-])CC(O)CCl
Reactant: [NH4+]
Agent: [Na+]
Product: NCC(O)CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium 3-chloro-2-hydroxypropanesulfonate (1.97 g, 10 mmol) was dissolved in 12.5% aq. ammonium solution and it was stirred at room temperature overnight. Ammonia was removed by concentrating the solution in evaporator and Sodium 3-amino-2-hydroxypropanesulfonate was obtained. Sodium 3-amino-2-hydroxypropanesulfonate (177 mg, 1 mmol) was dissolved in water (10 ml), NaHCO3 (84 mg, 1 mmol) and lauroyl chloride (231 μl, 1 mmol) were added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the compound was absorbed by adding Wakogel 50C18 (2 cm3), the gel was loaded into a column and washed with water (50 ml), and eluted with methanol (10 ml). The elution was cooled to give PHL (sodium 2-hydroxy-3-lauramide-1-propansulfonate) as a crystalline. MALDI-TOF-MS [M+Na]+ m/z=381.75.
Reaction SMILES: II.C(Br)C.Br[C:7]1[CH:19]=[CH:18][C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[CH3:20][N:21]([CH3:38])[CH2:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](N(OC)C)=[O:32])=[CH:27][C:26]1=[O:37]>C1COCC1>[CH3:38][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:32])[C:7]2[CH:19]=[CH:18][C:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:9][CH:8]=2)=[CH:27][C:26]1=[O:37]
Reactant: Brc1ccc(OC2CCCCO2)cc1
Reactant: CON(C)C(=O)c1ccn(CCCN(C)C)c(=O)c1
Agent: II
Solvent: CCBr
Solvent: C1CCOC1
Product: CN(C)CCCn1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cc1=O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Mg (440 mg, 3.5 eq) was added to a 3-neck round bottom flask containing 50 mL anhydrous THF, and the mixture was heated to 55° C. Iodine chips (2 grains) were added in one lot followed by 0.1 mL ethyl bromide. 2-(4-Bromophenoxy)-tetrahydro-2H-pyran (4.0 g, 3.0 eq) was dissolved in 30 mL anhydrous THF, and 3 mL of this solution was added at once to the Mg-THF suspension. The reaction was initiated after 30 min and reflux started. the remaining solution of 2-(4-bromophenoxy)-tetrahydro-2H-pyran was added dropwise maintaining the reflux temperature over 5 min. After addition, the reaction mixture was further reflux for 2 h., cooled to rt, 1-(3-(dimethylamino)propyl)-N-methoxy-N-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxamide (1.4 g, 1.0 eq) in 20 mL THF was added dropwise at rt, stirred at rt for 30 min., quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (1.6 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=9.2 Hz, 2H), 7.48 (d, J=6.8 Hz, 1H), 7.11 (d, J=9.2 Hz, 2H), 6.75 (d, J=1.6 Hz, 1H), 6.44 (dd, J=6.8 Hz, 2.0 Hz, 1H), 5.55 (t, J=2.8 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.82-3.88 (m, 1H), 3.62-3.66 (m, 1H), 2.32 (t, J=6.4 Hz, 2H), 2.24 (s, 6H), 1.88-2.08 (m, 5H), 1.62-1.74 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.11 g (12.9 mmol) of the compound of Example 21A are provided in 142 ml of tetrahydrofuran and, at room temperature, 3.08 g (129 mmol) of lithium hydroxide and 47 ml of water are added. The mixture is stirred at room temperature overnight and a 1N aqueous hydrogen chloride solution is subsequently added until the pH is acidic, the mixture extracted with ethyl acetate, and the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. 4.51 g (90% of theory) of the title compound are obtained.