Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[NH2:6])[CH3:2].[CH2:26]([CH:36]1[CH2:41][C:40](=[O:42])[O:39][C:37]1=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[NH:6][C:40](=[O:42])[CH2:41][CH:36]([C:37]([OH:39])=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:2]
Reactant: CCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)OCC
Reactant: CCCCCCCCCCC1CC(=O)OC1=O
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)CC(CCCCCCCCCC)C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
Nε-Lauroyl-L-lysine ethyl ester (29.9 g) was dissolved in dehydrated dichloromethane (650 ml), n-decyl succinic anhydride (21.2 g) was added, and the mixture was stirred at room temperature for 24 hr. The obtained white turbid solution was heated and cooled in a freezer to give crystals. The mixture was filtered, dried, and recrystallized to give Nε-lauroyl-Nα-(3-carboxytridecanoyl)-L-lysine ethyl ester (43 g, yield 85%). 4 g thereof was dissolved in distilled ethanol (100 ml), and 4M aqueous NaOH solution (1.68 ml) was added with stirring. The mixture was stirred at room temperature for 3 hr, filtered, dried under reduced pressure, and recrystallized. yield 4.1 g, 97%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]2([CH2:15][CH2:14]2)[C:3]1=[O:16].O.O.Cl[Sn]Cl>CCOC(C)=O>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3](=[O:16])[C:4]12[CH2:14][CH2:15]1
Reactant: CN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CN1C(=O)C2(CC2)c2cc(N)ccc21
Yield: 85 %

Procedure:
1′-Methyl-5′-nitro-spiro[cyclopropane-1,3′-indoline]-2′-one (3 g) is dissolved in EtOAc (105 ml) and SnCl2.2H2O (9 g; 46.5 mmol) is added. The reaction mixture is refluxed overnight, cooled and filtered over Al2O3. After an aqueous work-up of the filtrate the compound (2.2 g) is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[O:12])[NH:6]2.Cl.[CH:22](N)=N.O>C(O)C>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][NH:15][C:14]=1/[CH:13]=[C:4]1\[C:5](=[O:12])[NH:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:11][CH:22]=[N:1][C:2]=3[C:3]\1=2
Reactant: N=CN
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3[nH]cnc3c21
Temperature: 25 °C

Procedure:
A mixture of (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.22 mmol) (from Example 15 above) and formamidine hydrochloride (177 mg, 2.2 mmol) (Aldrich) in ethanol (3 mL) was heated at reflux for 45 min. The mixture was cooled to room temperature, and water was slowly added to induce precipitation. The precipitate was collected by suction filtration, washed with water and dried in a vacuum oven overnight to give (Z)-8-[(3-methoxy-1H-pyrrol-2-yl)methylene]-3,6,7,8-tetrahydro-pyrrolo-[3,2-e]benzimidazol-7-one. (Yield 48 mg, 99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br.[OH:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[CH2:22][CH2:23][NH2:24]>CN(C)C=O>[OH:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[CH2:22][CH2:23][NH:24][C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1O
Reactant: O=C(O)/C=C/c1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccnc1)NCCc1ccccc1O
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 62.1 %

Procedure:
Trans-3-(3-pyridyl)acrylic acid (22.35 g) and N,N′-carbonyldiimidazole (24.54 g) were dissolved in dimethylformamide (300 ml) and stirred at 40° C. for 40 minutes. Then, potassium carbonate (41.4 g) and 2-hydroxyphenethylamine hydrobromide (32.70 g) were added under room temperature and stirred for 1 hour. Insoluble materials were filtered out and the filtrate was concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue under ice-cooling and stirring. The precipitated crystal was filtered out, washed with water, purified by silica gel column chromatography (chloroform:methanol=20:1) and then recrystallized in methanol to yield the titled compound (24.98 g, 62%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:12][C@H:13]1[CH2:16][O:15][C:14]1=[O:17].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>CN(C=O)C>[N:18]1([CH2:16][C@@H:13]([C:14]([OH:15])=[O:17])[NH2:12])[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: c1cn[nH]c1
Reactant: N[C@H]1COC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: N[C@@H](Cn1cccn1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
(S)-3-Amino-2-oxetanone tosylate salt (100 mg, 0.385 mmol) was added to pyrazole (131 mg, 1.93 mmol) in distilled DMF (3.0 mL) and the mixture was stirred at 25° C. for 2.5 h. The solvent was removed in vacuo at 25° C. and the residue was dissolved in H2O (3 mL) and applied to a column of BioRad AG50-X8 (trademark) (1×10 cm, H+ form) The resin was washed with H2O (30 mL) and eluted with a gradient of aqueous NH4OH (0 to 0.25N over 70 mL, then 100 mL of 0.25N NH4OH). The product emerged chromatographically pure with 0.25N NH4OH and was lyophilized (2×) and dried in vacuo over P2O5 to yield 77% (46.2 mg) of β-(pyrazol-1-yl)-L-alanine (mp 234°-236° C. (dec)). For an improved melting point this material could be recrystallized from H2O/ EtOH: mp 241°-243° C. (lit. mp 236°-238° C. (dec), 243° C. (dec)); [α]D25 -72(±1) (c 0.54, H2O) (lit. [α]D -78° (c 3.4, H2O),-72.0° (c 1. H2O)); IR (KBr disk) 3700-2200 (m, vbr), 1617 (s), 1580 (s), 1485 (m), 1395 (m), 767 (m) cm-1 ; 1H NMR (300 MHz, D2O)δ 7.65 (d, 1H, 2 Hz, ArHH'H"), 7.61 (d, 1H, 2 Hz, ArHH'H"), 6.38 (t, 1H, 2 Hz, ArHH'H"), 4.66 (d, 2H, 5 Hz, CH2N), 4.18 (t, 1H, 5 Hz, CH); POSFAB-MS glycerol/HC1 ) 156 (MH+), 311 (M2H+); Rf 0.67 (Solvent A; characteristic blue-purple color with ninhydrin).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2].[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]([OH:16])[CH2:17][N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2]
Reactant: CCNCC
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OC[C@H]1CO1
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
After dissolving N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (200 mg, 0.425 mmol) in tetrahydrofuran (5.0 ml) under a nitrogen atmosphere, diethylamine (1.0 ml) was added and the mixture was stirred overnight at 60° C. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent-ethyl acetate:methanol=9:1), the fraction containing the target substance was concentrated, methanol (5 ml) was added for crystallization, and the crystals were filtered out and blow-dried to obtain the title compound (126.4 mg, 0.233 mmol, 54.7%) as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17](=[O:18])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: O=C(O)CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccccc1
Yield: 51.2 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 8-bromo-5-carboxymethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (130 mg, 0.40 mmol) and aniline (40 μL, 0.44 mmol) to give 82 mg of the title compound (51%): mp 186° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.23 (s, 1H), 10.34 (s, 1H), 7.55 (d, 2H, J=8 Hz), 7.32 (t, 2H, J=8 Hz), 7.22 (s, 2H), 7.07 (t, 1H, J=8 Hz), 5.30~5.36 (m, 1H), 2.86 (dm, 1H, J=18 Hz), 2.75 (dm, 1H, J=14 Hz), 2.62 (m, 1H, J=14 Hz), 2.02~2.18 (m, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=1.Br[C:26]#[C:27][CH3:28]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:11])[N:10]([CH2:28][C:27]#[CH:26])[C:6]=2[CH:5]=1
Reactant: CC#CBr
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCn1c(=O)n(C2CCN(C(=O)OCC)CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.9 parts of sodium hydride dispersion 75% in 100 parts of hexamethylphosphoric triamide are added portionwise 16.2 parts of ethyl 4-(5-chloro-2-oxo-1-benzimidazolinyl)-1-piperidinecarboxylate (exothermic reaction: temperature rises to 40° C). After stirring for one hour at room temperature, there are added dropwise 8.9 parts of 3-bromo-2-propyne (exothermic reaction: temperature rises to about 40° C). Upon completion, stirring is continued overnight at 60° C. The reaction mixture is cooled, poured onto ice-water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane. The solid product is filtered off and dried, yielding ethyl 4-[5-chloro-1,3-dihydro-2-oxo-3-(2-propynyl)-2H-benzimidazol-1-yl]-1-piperidine-carboxylate; mp. 126.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.Cl>O.C(O)C>[ClH:1].[OH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Temperature: 25 °C

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 3-aminophenol (32 mg, 0.290 mmol), and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and the resulting crystals was filtered, washed with water, with water:ethanol (2:1) and dried to give a tan crystals (22 mg, 30%). 1H NMR (DMSO-d6): 10.17 (s, 1H), 9.36 (d, J=1.5 Hz, 1H), 8.72–8.66 (m, 2H), 7.66–7.62 (m, 1H), 7.20 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.45–6.41 (m, 1H).
Reaction SMILES: [NH2:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:10]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][C:20]([NH:1][O:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][O:4]2)=[O:21])=[CH:10]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1c[nH]c2ccccc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1c[nH]c2ccccc12)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NH2OTHP (0.38 g, 3.21 mmol) was added to a solution of trans-3-indoleacrylic acid (17) (0.50 g, 2.67 mmol), PyBOP (1.47 g, 2.83 mmol), triethylamine (0.74 ml, 6.41 mmol) in THF (25 mL). The mixture was stirred at room temperature for 2 h and then was concentrated under reduced pressure. The residue was dissolved in EtOAc and quenched with water, followed by extraction with EtOAc (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc:n-hexane=1.5:1:1% NH3(aq)) to afford 18. 1H NMR (500 MHz, CD3OD): δ 1.58-1.70 (m, 3H), 1.79-1.90 (m, 3H), 3.63-3.65 (m, 1H), 4.03-4.08 (m, 1H), 4.97-4.98 (m, 1H), 6.47 (d, J=14.9 Hz, 1H), 7.15-7.21 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.59 (s, 1H), 7.84-7.87 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CC(C)=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][Br:19])[CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: BrCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3cccc(CBr)c3)cc2s1
Yield: 91.7 %

Procedure:
To a solution of 2-cyano-6-hydroxybenzothiazole (1.04 g) in 30 mL of acetone was added potassium carbonate (1.63 g), followed by α, α′-dibromo-m-xylene (4.7 g). The resultant solution was stirred at RT for 1 hour and the solvent was removed under reduced pressure. The residue was resuspended in dichloromethane and washed with water. The aqueous phase was extracted with more dichloromethane (2×) and the organic extracts were combined, dried over sodium sulfate, and purified by flash chromatography using dichloromethane. 1.945 g of product was obtained.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[SH:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1.C(N(CC)CC)C>CN(C)C=O>[NH:11]1[C:10]([S:9][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:14][N:13]=[N:12]1
Reactant: Sc1nnn[nH]1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cc(Sc2nnn[nH]2)ccn1
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A mixture of 4-chloropyridine hydrochloride (7.25 g), 5-mercapto-1H-tetrazole (4.93 g) and triethylamine (14.64 g) in dimethylformamide (120 ml) was stirred for one hour at 82° to 85° C. and then cooled in an ice bath. The resulting precipitates were removed by filtration and the filtrate was mixed with water (60 ml). The aqueous solution was adjusted to pH 2 with 2N hydrochloric acid and evaporated to dryness under reduced pressure. The residue was triturated in chloroform (300 ml) and the resulting precipitates were collected by filtration and washed with the same solvent. To the precipitates was added ethanol (650 ml) and an insoluble material was removed by filtration. The filtrate was evaporated to dryness to give 4-(1H-tetrazol-5-ylthio)pyridine (4.03 g), mp. 159° to 161° C. (dec.).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:24][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:26][CH2:27][OH:28])=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: Oc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCCOc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 25 °C

Procedure:
A solution of 3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenol 39 (1.2 mmol), 2-bromoethanol (1.4 mmol) and cesium carbonate (1.6 mmol) in acetonitrile (10 mL) is heated to 85° C. for 12 h then cooled to rt. The reaction is evaporated to dryness then re-dissolved in DCM. The organic mixture is washed with water and brine then dried over magnesium sulfate, filtered and reduced to dryness. Purification by silica gel chromatography with hexane:EtOAc=1:1 as eluant affords 2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethanol 40a as white solid. MS (m/z) (M+1)+: 373.8.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[CH2:20][CH3:21]>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[CH2:20][CH3:21])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1n(N)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 20 h

Procedure:
705 mg (4.7 mmol) of 4-dimethylaminobenzaldehyde are added to a solution of 348 mg (2.1 mmol) of 1,3-diamino-2-ethyl-imidazolium chloride in 4.4 ml of glacial acetic acid, whereupon the mixture is stirred for 20 hours. The yellow crystals obtained are filtered off and recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethyl-amino)benzylidene]amino]-2-ethylimidazolium chloride of melting point 248°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl-].[CH:28]1([S:31](C2CC2)(=[O:33])=[O:32])[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][NH:20][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(C1CC1)C1CC1
Reactant: NC[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: [Cl-]
Product: O=S(=O)(NC[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C1CC1

Procedure:
Prepared according to the procedure described for Example 1 from (1R)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-ethan-2-amine (40a, 31 mg, 0.09 mmol) cyclopropylsulphone chloride (28 μl, 0.27 mmol). Yield: 10 mg (25%).
Reaction SMILES: [CH2:1]([C@:3]([OH:31])([C:15]1[CH:23]=[C:22]2[N:18]([CH2:19][CH2:20][C:21]32OCC[O:24]3)[C:17](=[O:28])[C:16]=1[CH2:29][OH:30])[C:4](N[C@@H](C1C=CC=CC=1)C)=[O:5])[CH3:2].OS(O)(=O)=O.ClCCl>C(COC)OC>[CH2:1]([C@:3]1([OH:31])[C:15]2[CH:23]=[C:22]3[N:18]([CH2:19][CH2:20][C:21]3=[O:24])[C:17](=[O:28])[C:16]=2[CH2:29][O:30][C:4]1=[O:5])[CH3:2]
Reactant: CC[C@@](O)(C(=O)N[C@H](C)c1ccccc1)c1cc2n(c(=O)c1CO)CCC21OCCO1
Agent: O=S(=O)(O)O
Solvent: COCCOC
Solvent: ClCCl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reaction time: 20 h
Yield: 62.9 %

Procedure:
Dissolved in 15 ml of dimethoxyethane was 815 mg of the compound (VI) obtained in the above procedure (1), followed by an addition of 5 ml of 2N H2SO4. The thus-prepared solution was heated with stirring for 20 hours under a nitrogen gas stream. After completion of the reaction, 150 ml of dichloromethane was added and the resultant mixture was washed with water. The organic layer was then dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from a mixed solvent of ethanol and petroleum ether to obtain 315 mg of the title compound as colorless needle-like crystals.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13]([NH:16][C:17](=[O:23])[C:18]([O:20]CC)=O)([CH3:15])[CH3:14])[CH2:9][C:8]2=[O:24])=[CH:4][CH:3]=1.[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI>CN(C=O)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]3[C:9](=[C:18]([OH:20])[C:17](=[O:23])[N:16]([CH3:28])[C:13]3([CH3:14])[CH3:15])[C:8]2=[O:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)NC(C)(C)C1CCN(Cc2ccc(F)cc2)C(=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of ethyl ({1-[1-(4-fluorobenzyl)-2-oxopiperidin-4-yl]-1-methyethyl}amino)(oxo)acetate (1.2 g, 3.3 mmol) in anhydrous DMF (10 mL) under an atmosphere of nitrogen was added LiHMDS (1M in THF, 3.5 mL, 3.5 mmol). After stirring at 0° C. for 15 min, methyl iodide (0.47 g, 3.3 mmol) was added to the reaction mixture. After stirring for an additional 15 min, more LiHMDS (1M in THF, 3.5 mmol, 3.5 mmol) was added. After another 2 h, an additional portion of LiHMDS (1M in THF, 3.5 mL, 3.5 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was concentrated under vacuum. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with a gradient of 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as an oil 1H NMR (400 MHz, CDCl3) δ 7.27 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.67 (d, J=14.7 Hz, 1H), 4.52 (d, J=14.7 Hz, 1H), 3.33 (d, J=6 Hz, 2H), 3.31 (s, 3H), 2.84 (m, 1H), 1.93 (m, 1H), 1.64 (m, 1H), 1.37 (s, 3H), 1.13 (s, 3H) ppm. ES MS M+1=333.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([N:7]=[C:8]=[O:9])[CH3:6].[F:10][C:11]([F:30])([F:29])[C:12]([C:18]1[CH:28]=[CH:27][C:21]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:20][CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:5]([NH:7][C:8]([N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[C:21]1[CH:27]=[CH:28][C:18]([C:12]([OH:17])([C:11]([F:10])([F:29])[F:30])[C:13]([F:14])([F:15])[F:16])=[CH:19][CH:20]=1)=[O:9])[CH3:6]
Reactant: CS(=O)(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CCN=C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCNC(=O)N(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)S(C)(=O)=O

Procedure:
To 3.0 g (23 mmole) AlCl3 in 50 ml nitrobenzene, add 1.4 g (20 mmole) EtNCO. To the solution, add 6.7 g (20 mmole) 4'-(hexafluoro-2-hydroxy-2-propyl)methanesulfonanilide (prepared as in Example 1). Heat for 4 hours at 80° and distill the solvent in vacuo. Triturate the product with 1N HCl and dissolve in Et2O. Dry, concentrate and recrystallize from Et2O-hexane to give the product; m.p. 161°-164° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[C:12](=[O:13])[CH:11]3[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]3[C:9]2=[O:18])=[C:6]([F:19])[CH:5]=[C:4]([Cl:20])[C:3]=1[OH:21].[CH2:22](Br)[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:3]([O:21][CH2:24][C:23]#[CH:22])=[C:4]([Cl:20])[CH:5]=[C:6]([F:19])[C:7]=1[N:8]1[C:12](=[O:13])[CH:11]2[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]2[C:9]1=[O:18]
Reactant: Nc1c(O)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1c(Cl)cc(F)c(N2C(=O)C3C=CCCC3C2=O)c1N

Procedure:
A mixture of 2-amino-6-chloro-4-fluoro-3-(tetrahydrophthalimido)phenol (0.31 g), propargyl bromide (0.2 ml), potassium carbonate (0.14 g), and acetonitrile (5 ml) was heated under reflux for 0.5 hr. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the title product (0.2 g).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].[NH3:10]>>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:10])=[O:8]
Reactant: N
Reactant: O=C(Cl)c1ccsc1Br
Product: NC(=O)c1ccsc1Br
Yield: 90.8 %

Procedure:
Add 2-bromothiophene-3-carbonyl chloride (540 mg, 2.39 mmol) to a solution of aqueous ammonia (25%, 3 mL, 17.44 mmol) with stirring. Stir the mixture for 30 minutes. Concentrate the mixture. Collect the resulting precipitate via filtration and wash the solids with water. Dry the white precipitate in vacuo to obtain the title compound (450 mg, 2.17 mmol).