Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)[CH3:2]>[C].[Pd].O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(/C=C/c2ccco2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CCc2ccco2)cc1
Yield: 65.7 %

Procedure:
To an anhydrous tetrahydrofuran (25 mL) solution of 4-((E)-2-furan-2-yl-vinyl)-benzoic acid ethyl ester (1.07 g, 4.4 mmol) described in Manufacturing Example 80-1-1 was added 10% palladium-carbon (50% hydrate, 500 mg), which was added for 2 hours under a hydrogen atmosphere at room temperature. The reaction product was filtered, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (t-butylmethyl ether: heptane=5:95) to obtain the title compound (706 mg, 65.4%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:45][C:46]([OH:50])([C:48]#[CH:49])[CH3:47]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:49]#[C:48][C:46]([OH:50])([CH3:47])[CH3:45])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(N1CCOCC1)COc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(s1)C(N1CCOCC1)COc1ccc(C#CC(C)(C)O)cc1-2
Temperature: 80 °C
Yield: 66.2 %

Procedure:
To a stirred mixture of 9-Bromo-4-morpholin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (270 mg, 0.635 mmol) in TEA (5 mL) and DMF (1 mL) were added Pd(OAc)2 (14.22 mg), PPh3 (49.9 mg 0.190 mmol), CuI (24.1 mg, 0.127 mmol), 2-methylbut-3-yn-2-ol (266.6 mg, 3.174 mmol). The reaction mixture was degassed with N2 and heated to 80° C. for 6 h. Then the mixture was cooled to room temperature, and EtOAc was added. The mixture was filtered though Celite, and the filtrate was washed with saturated brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-morpholin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (180 mg, 66%) as a light yellow solid. LC-MS (ESI & APCI): 429.0 (M+1).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=[CH:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.O>ClCCl>[Br:2][C:1]([Br:5])=[CH:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Carbon tetrabromide (46.7 g, 141 mmol) was dissolved in 200 mL dichloromethane. The solution was cooled in an ice-water bath and triphenylphosphine (73.9 g, 282 mmol) in 200 mL dichloromethane was introduced via an addition funnel over 20 min. The reaction mixture was stirred at 0° C. for 10 min and a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (16 g, 70.4 mmol) in 100 mL dichloromethane was added via an addition funnel. The solution was stirred at 0° C. for 1 hour. Water (250 mL) was added and aqueous layer was extracted 3 times with 100 mL dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. 300 mL ether was added to the residue, and the resulting suspension was filtered. The solid was washed 3 times with 150 mL ether. The combined filtrate was concentrated and passed through a plug of silica gel, washed thoroughly with 10% acetone/hexanes to afford yellow oil which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O>[CH3:21][NH:20][C:16]1[N:15]=[C:14]([O:13][C:12]2[CH:22]=[CH:23][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: CNc1nccc(Oc2ccc(OCc3ccccc3)cc2)n1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1nccc(Oc2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
[4-(4-Benzyloxy-phenoxy)-pyrimidin-2-yl]-methyl-amine (Step B, 0.75 g, 2.44 mmol) was dissolved in 5 mL MeOH and 10 mL EtOAc. To the argon-degassed solution was added 10% by weight Pd/C (0.15 g). The reaction was stirred vigorously at RT under 1 atm H2 gas for 4 days. The reaction was filtered through Celite® and concentrated in vacuo to yield the title compound. MS (MH+)=218.1; Calc'd 217.23 for C11H11N3O2.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: c1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccccc1

Procedure:
The title compound, pale pink solid, m.p. 119° C. and MS: m/e=321 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-phenyl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@H:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@@H:17]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[O:15])C1C=CC=CC=1.[OH:30]O.O.[OH-].[Li+]>C1COCC1.O>[Si:23]([O:22][C@@H:17]1[C@@H:16]([C:14]([OH:15])=[O:30])[CH2:21][C@H:20]2[C@@H:18]1[CH2:19]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of (R)-4-benzyl-3-((1S,2S,3S,5S)-2-(tert-butyldimethylsilyloxy)bicyclo[3.1.0]hexane-3-carbonyl)oxazolidin-2-one (40 g, 96.4 mmol) in THF (200 mL) and water (50 mL) was added 30% aqueous hydrogen peroxide (88 mL, 771 mmol) dropwise at 0° C., followed by the addition of a solution of lithium hydroxide monohydrate (16 g, 386 mmol) in water (100 mL). After stirring for 1 hour at 0° C., the reaction mixture was stirred at room temperature overnight. The excess hydrogen peroxide was completely consumed by the addition of saturated aqueous sodium bisulfate. The mixture was then adjusted to pH=14 with 1 N NaOH and washed with ether (400 mL). The aqueous layer was then acidified to pH=3 with 1 M aqueous potassium hydrogen sulfate, and extracted with ethyl acetate (3×400 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (22 g, 88%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][C:10]([CH:8]2[CH2:7][CH2:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:9]2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)C1CCc2[nH]cnc2C1
Product: O=C(NCCCc1ccccc1)C1CCc2[nH]cnc2C1

Procedure:
The title compound was prepared by a similar procedure as described in Example 4 from 100 mg of 2-formyl-5-methoxyphenoxyethylpolystyrene (0.55 mmol/g) resin, 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid (111 mg, 0.55 mmol) and 3-phenylpropylamine (74.4 mg, 0.55 mmol).
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](C3C=CC(CC(NCC4C=CC=CC=4)=O)=NC=3)=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.ClCCN1CCOCC1.[Br:44]C1C=CC(O)=CC=1>>[Br:44][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)=[CH:13][CH:14]=1
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: ClCCN1CCOCC1
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
In another aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with hydrochloric acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CO.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>S(=O)(=O)(O)O.CCOCC.O>[CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]([CH2:6][OH:7])[CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCOc1c(OC)cccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCCCCOc1c(CO)cccc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Methoxy-2-pentyloxybenzoic acid (1.5 g, 6.3 mmol), methanol (10 ml) and conc. sulfuric acid (1 drop) were mixed, and this solution was refluxed under heating for 7 hours. Methanol was evaporated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution (3 ml) was added. The aqueous layer was extracted twice with ethyl acetate (20 ml). The organic layers were combined, washed twice with a saturated aqueous sodium hydrogencarbonate solution (5 ml) and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. THF (15 ml) was added to the obtained residue in a stream of argon, and the mixture was cooled to 0° C. Lithium aluminum hydride (0.49 g, 13 mmol) was added to this solution, and the mixture was stirred for 1 hour. Water (0.4 ml), a 1N aqueous sodium hydroxide solution (0.4 ml) and water (1.2 ml) were successively added dropwise to the reaction mixture. Ether (60 ml) was added, and the mixture was vigorously stirred for 1 hour. The inorganic salt was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of (3-methoxy-2-pentyloxyphenyl)methanol. The product was not further purified, and used in the next reaction.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH3:15].CO>CO>[C:9]1([C:1]2[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=2)[CH2:7][NH2:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N
Reactant: O=Cc1cccc(-c2ccccc2)c1
Solvent: CO
Product: NCc1cccc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3-biphenylcarboxaldehyde (0.0.11 eq.) in 30 mL of methanol was added 10 eq. of 7N NH3/MeOH and NaCNBH4 (2 eq.). A yellow gum precipitated from solution. The solution was then heated at 60° C. until gum dissolved and the solution was stirred at room temperature overnight. The reaction mixture was then concentrated and the resulting residue diluted with ice water and ethyl acetate. The organic layer was then washed with brine and extracted with 5N HCl. The pH of the aqueous layer was then adjusted to 12 and the aqueous layer was extracted with cold ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to give 3-(phenyl)benzyl amine as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[C:27]([CH3:33])=[N:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:28]2[C:27]([CH3:33])=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:31])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1nn(C)cc1C(=O)O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cn(C)nc2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1,3-Dimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=450.5.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:17]([N:19]([CH2:22][CH2:23][Cl:24])[CH2:20][CH3:21])[CH3:18]>>[ClH:24].[CH2:17]([N:19]([CH2:22][CH3:23])[CH:20]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH3:21])[CH3:18]
Reactant: CCN(CC)CCCl
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Agent: Cl
Product: CCN(CC)C(C)c1cccc2[nH]nc(-c3ccccc3)c12
Yield: 30.4 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenylindazole (3.88 g) and diethylaminoethyl chloride hydrochloride (5.16 g) were treated to obtain 2.0 g of 1-diethylaminoethyl-3-phenylindazole hydrochloride (m.p. 114°-118° C).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])=[CH:4][CH:3]=1.[CH:22]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:35]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:15])=[O:7])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1
Reactant: CCCCN(CCCCC(=O)O)C(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(CCCCC(=O)N(CCCCC(=O)O)C(c1ccccc1)c1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-5-(n-butylamino)valeric acid and ethyl 5-benzhydrylaminovalerate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-5-(n-butylamino)pentanoyl]-5-benzhydrylaminovaleric acid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[CH:11]([CH3:13])O.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]([CH3:13])[C:10]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)C(C)O
Reactant: O=Cc1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
6.1 g of 4-hydroxybenzaldehyde, 10.8 g of (-)-ethyl lactate-mesylate ([α]D25 =-54°, optical purity: 96%), 4 g of potassium carbonate, 0.2 g of potassium iodide and 100 g of dimethyl formamide, were mixed, and the reaction was stirred at 100° C. for 5 hours and then cooled to room temperature. The reaction mixture was subjected to liquid separation with an addition of toluene and water. The organic layer was washed twice with water, and after distilling off toluene, subjected to distillation under reduced pressure, whereby 8.9 g of (+)-ethyl 2-(4-formylphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg.
Reaction SMILES: FC1C=C(C(C)(C)CC(O)(C(F)(F)F)C=O)C2OCCC=2C=1.NC1C=CC=C2C=1C=CC=N2.[F:34][C:35]1[CH:36]=[C:37]([C:44]([CH3:65])([CH3:64])[CH2:45][C:46]([OH:63])([C:59]([F:62])([F:61])[F:60])[CH:47]=[N:48][C:49]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:50]=2[CH:51]=[CH:52][CH:53]=[N:54]3)[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1.[BH4-].[Na+]>>[F:34][C:35]1[CH:36]=[C:37]([C:44]([CH3:65])([CH3:64])[CH2:45][C:46]([OH:63])([C:59]([F:60])([F:62])[F:61])[CH2:47][NH:48][C:49]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:50]=2[CH:51]=[CH:52][CH:53]=[N:54]3)[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1
Reactant: CC(C)(CC(O)(C=Nc1cccc2ncccc12)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: Nc1cccc2ncccc12
Agent: [BH4-]
Product: CC(C)(CC(O)(CNc1cccc2ncccc12)C(F)(F)F)c1cc(F)cc2c1OCC2

Procedure:
Analogously to Example 1, 4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-aminoquinoline into 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]quinoline, which is reduced with sodium borohydride to the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:14])=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][C:9]3=[O:13])[CH:7]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)c(N2CCCC2=O)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCN1c1cc(NCc2ccc(Cl)cc2)ccc1F
Yield: 44.1 %

Procedure:
A solution of 1-(5-amino-2-fluoro-phenyl)-pyrrolidin-2-one (0.34 g, 1.8 mmol), 4-chlorobenzaldehyde (0.25 g, 1.8 mmol) and sodium triacetoxyborohydride (0.75 g 3.6 mmol) was stirred in dry dichloromethane (25 ml) overnight. The reaction was quenched with water (25 ml) and the dichloromethane layer separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2) eluting with ethyl acetate/dichloromethane (1:10) to afford the title compound as a yellow oil (253 mg, 44%). HPLC retention time 4.4 min, Mass spectrum (ES+) m/z 319 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CS(C)=O>[I:11][C:4]1[CH:3]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(I)cc(N2CCOCC2)c1
Temperature: 130 °C
Yield: 80 %

Procedure:
To a solution of 1-fluoro-3-iodo-5-nitrobenzene (4.0 g, 15 mmol) in DMSO (7.5 mL) was added morpholine (3.26 mL, 37.5 mmol), and the mixture (which instantly became purple) was heated to 130° C. for 30 min in the microwave. Purification was attempted by directly loading the mixture onto a CombiFlash column (80 g; load neat w/CH2Cl2 rinse; 100:0 to 60:40 hexanes:EtOAc over 35 minutes) but the mixture crashed at the top of the column and not all the mixture could be loaded. Nonetheless, after an inital spike in pressure, purification was possible, and the residual material was purified in a second purification (24 g; load w/CH2Cl2; 100:0 to 60:40 hexanes:EtOAc over 20 minutes). Concentration of the combined fractions from the two purifications provided 4-(3-iodo-5-nitrophenyl)morpholine (4.01 g, 12.0 mmol, 80%) as a bright yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H); 7.67 (s, 1H); 7.47 (s, 1H); 3.89 (s, 4H); 3.26 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[O:35]([CH2:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:43](=[O:44])[CH2:42][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)COc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a cooled (0° C.) mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.7 ml (19 mmol) of triethylamine in 15 ml of CH2Cl2 was added 1.58 g (11.4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered. The filtrate was washed with H2O, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed to give 2.4 g of crude methyl 2-{(4-methoxybenzenesulfonyl)-[2-(phenoxyacetylamino)benzyl]amino}acrylate as an oil. Anal. for C26H26N2O7S: Calc'd: C,61.2; H,5.1; N,5.5; Found: C,62.6; H,5.1; N,4.0; Mass spectrum (ES) 511 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:8](=[O:10])[N:7]3[CH2:11][CH2:12][CH2:13][CH2:14][C:6]3=[N:5][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:18]([N:1]1[C:9]2[C:8](=[O:10])[N:7]3[CH2:11][CH2:12][CH2:13][CH2:14][C:6]3=[N:5][C:4]=2[N:3]=[CH:2]1)[CH2:19][CH2:20][CH3:21]
Reactant: O=c1c2[nH]cnc2nc2n1CCCC2
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cnc2nc3n(c(=O)c21)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
After 1.20 g (6.32 mmol) of Compound 24 obtained in Example 24 was suspended in 20 ml of dimethylformamide, 0.265 g (6.63 mmol) of 60% sodium hydride was added to the suspension at 0° C. After 30 minutes, 0.755 ml (6.63 mmol) of iodobutane was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent; chloroform:methanol=40:1) to afford 1.10 g (70.8%) of Compound 26 as white crystals.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3].[NH3:10]>O1CCCC1>[NH2:10][C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3]
Reactant: N
Reactant: O=C(Cl)N1CCNC1=O
Solvent: C1CCOC1
Product: NC(=O)N1CCNC1=O

Procedure:
29.7 parts by weight of N-chlorocarbonyl-imidazolid-2-one, were reacted at pH = 8.5 and room temperature with 20 parts by volume of 25% strength aqueous solution of NH3 in 80% strength aqueous tetrahydrofurane. After stripping off the tetrahydrofurane in vacuo, the product which precipitated was filtered off and washed with a little ice water. Yield after drying over P2O5 in a desiccator: 62%. Melting point 200° C.