Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:24]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[N:24][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1ncc2c(O)c(C(=O)c3ccc(OC)cc3)cnc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4ccc(OC)cc4)c3cnc21

Procedure:
1-Ethyl-4-hydroxy-5-(4-methoxybenzoyl)-1H-pyrazolo[3,4-b]pyridine (3.60 g) was refluxed overnight in 30 ml of pyridine containing 4.0 g of hydroxylamine hydrochloride. At the end of this time the pyridine was evaporated and the residue triturated with 5% hydrochloric acid. The product obtained in this manner was chromatographed silica gel (5% methanol/dichloromethane) to remove a fluorescent impurity. Combination of the appropriate fractions and recrystallization from dichloromethane/hexane gave 2.95 g of pure product, mp 156°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.N1C=CC=CC=1.Cl.[NH2:19][OH:20]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:19][OH:20])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CCc2cc(F)ccc21
Yield: 96.9 %

Procedure:
4.5 g (30 mmol) of 5-fluoro-1-indanone and 20 ml of pyridine and 20 ml of ethanol were heated to 80° C. with 2.3 g (33 mmol) of hydroxylamine hydrochloride for 6 h. The solvents were distilled off, the residue was stirred with water and the precipitate was filtered off with suction and dried under reduced pressure. This procedure gave 4.8 g of 5-fluoro-1-indanoneoxime; m.p. 150-155° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([N:28]1[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([N:28]1[CH2:32][CH2:31][C@@H:30]([NH:33][C:2]2[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Temperature: 90 °C
Yield: 74 %

Procedure:
To a solution of ethyl (2E)-3-(4-bromophenyl)acrylate (1.0 g) in dioxane (70 mL) was added palladium(II) acetate (88 mg), 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-diphenylamine (231 mg), cesium carbonate (1.79 g), and (3R)-1-benzyl-3-pyrrolidinamine (760 mg). The mixture was heated at 90° C. for 24 hours. The resulting mixture was poured into sat NH4Cl aq solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by silica gel column chromatography eluted with chloroform:methanol=9:1 to give ethyl (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylate (1.017 g) as pale yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3]CCNC(=O)C.F[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=1)[N:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[N:26]=[CH:25]3)=[N:14][CH:15]=[N:16]2>CC(N(C)C)=O>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:13]3[C:12]4[C:11]([OH:3])=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]=[CH:15][N:14]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: Fc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: CC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 120 °C
Yield: 36 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 1.68 g, 42 mmol) in DMA (25 ml) was slowly added N-(2-hydroxyethyl)acetamide (1.80 g, 17.5 mmol). When the effervescence had subsided, 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine (2.60 g, 7.0 mmol) was added and the mixture was heated at 120° C. for 18 hours. The reaction was quenched by addition of saturated aqueous NH4Cl (5 ml) and evaporated (high vacuum). The residue was stirred with water (100 ml) giving a gelatinous precipitate, which was filtered off and washed with water. The product was purified by chromatography (silica, dry loaded, 5 to 10% methanol/DCM) and crystallized by trituration with ether to give 4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-ol (928 mg, 32%); NMR spectrum (373 K) 5.72 (s, 2H), 6.77 (m, 3H), 7.03 (d, 1H), 7.23 (dd, 1H), 7.44 (t, 1H), 7.50 (d, 1H), 7.59 (d, 1H), 7.70 (t, 1H), 8.07 (s, 1H), 8.13 (s, 1H), 8.27 (s, 1H), 8.52 (d, 1H), 11.87 (br s, 1H); Mass spectrum MH+ 369.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([CH2:7][C:8]1[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH:14]([NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[OH:19])[CH3:15])=[C:10]([Cl:29])[CH:9]=1)=[O:6].Cl>O.CO>[C:5]([CH2:7][C:8]1[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH:14]([NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[OH:19])[CH3:15])=[C:10]([Cl:29])[CH:9]=1)([OH:6])=[O:4]
Reactant: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(COc1ccc(CC(=O)O)cc1Cl)NCC(O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A solution of 6.0 g of potassium hydroxide in 10 ml of water was added to a solution of 2.3 g of 2-[2-(4-methoxycarbonylmethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol (prepared as described in Example 22) in 90 ml of methanol, and the resulting mixture was allowed to stand overnight. At the end of this time, the reaction mixture was poured into ice-water and the pH of the mixture was adjusted to a value of 7 by the addition of 1N aqueous hydrochloric acid, after which it was irradiated with ultrasonic waves. The crystals which precipitated were collected by filtration and recrystallized from methanol, to give 0.97 g of the title compound as crystals, melting at 188°-192° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][C:8](=O)[NH:9][CH2:10][C:11]=2[CH:12]=1.B>C1COCC1>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:11]=2[CH:12]=1
Reactant: O=C1Cc2ncc(C(F)(F)F)cc2CN1
Agent: B
Solvent: C1CCOC1
Product: FC(F)(F)c1cnc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a yellow suspension of 3-(trifluoromethyl)-5,8-dihydro-1,6-naphthyridin-7(6H)-one (2.08 g, 9.62 mmol) in THF (14 mL) was added slowly a 1.0 M solution of borane in THF (48.5 mL) and the resulting clear yellow solution was stirred at room temperature under N2 overnight. After overnight reaction, two peaks were detected. The major peak (>80%) was the borane complex, the minor peak was the desired product peak (<15%). In order to breakdown the borane complex, the cloudy reaction mixture was treated by dropwise addition of 6 M HCl (12 mL). Large amounts of bubbles and heat were generated. The resulting slightly cloudy yellow solution was stirred at room temperature overnight. After evaporation of solvents, the yellow crude product was dissolved in 25 mL of DMSO and slowly treated with TFA (4 mL) to get a yellow brown clear solution, which was purified by prep-HPLC to provide approx. 2.60 g (63%) of desired light yellow sticky product as di-TFA salt. LC-MS 203.0 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][CH:18]([CH:21]([CH3:30])[CH2:22][NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[CH2:17][CH:16]=2)=[CH:11][CH:10]=1)#[N:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.C1COCC1>[NH2:8][CH2:7][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][CH:18]([CH:21]([CH3:30])[CH2:22][NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[CH2:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(CNS(=O)(=O)C(C)C)C1CC=C(c2ccc(C#N)cc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CNS(=O)(=O)C(C)C)C1CC=C(c2ccc(CN)cc2)CC1
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a suspension of 33 mg (0.87 mmol) of lithium aluminum hydride in 0.5 ml of diethyl ether, 100 mg (0.29 mmol) of the material prepared in Example 14 in 0.5 ml of diethyl ether and 0.5 ml of THF. The mixture was stirred for 3 h. Na2SO4 10H2O was added, and the mixture stirred for 30 min at ambient temperature. The solid was filtered and the organic solution was concentrated in vacuo. Precipitation with diethyl ether afforded 65 mg (64%) of the title compound. Analysis calculated for C19H30N2O2S 0.75H2O: %C, 62.69; %H, 8.72; %N, 7.69. Found: %C, 62.73; %H, 7.96; %N, 7.32. Field Desorption Mass Spectrum: M=350.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:33]([O-:35])=[O:34])=[C:6]([CH:32]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:20][CH:19]=2)[CH:15]=1)=[O:8].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[CH3:31][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:32]=[C:2]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:3]=[CH:4][C:5]=2[N+:33]([O-:35])=[O:34])=[CH:15][C:14]=1[NH:16][C:17](=[O:30])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])ccc2C)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(N4CCOCC4)ccc3[N+](=O)[O-])ccc2C)cc1
Temperature: 100 °C
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 105° C. for 16 hours rather than to 100° C. for 6 days, N-[5-(5-chloro-2-nitrobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with morpholine. The solid so obtained was dissolved in methylene chloride and the solution was washed with a saturated aqueous sodium bicarbonate solution. The organic solution was dried (MgSO4) and evaporated. There was thus obtained the title compound in 64% yield; NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 2.2 (s, 3H), 2.4-2.6 (m, 4H), 3.4-3.5 (m, 4H), 3.6 (s, 2H), 3.7-3.8 (m, 4H), 7.0-7.1 (m, 2H), 7.2 (m, 1H), 7.4-7.5 (m, 2H), 7.7 (m, 1H), 7.9 (d, 2H), 8.05 (d, 1H), 9.85 (s, 1H), 10.38 (broad s, 1H); Mass Spectrum: M+H+546.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2C=[CH:45][C:44]([O:47][C@H](C)CO)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:43][CH:44]([OH:47])[CH3:45])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O[C@H](C)CO)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCC(C)O)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 211. 1H NMR (400 MHz, Methanol-d4) δ 8.28 (s, 1 H) 8.19 (m, 1 H) 8.06 (m, 1 H) 8.00 (m, 1 H) 7.92 (s, 1 H) 7.87 (t, J=8.0 Hz, 1 H) 7.26 (m, 2 H) 4.31 (m, 2 H) 4.10 (m, 1 H) 3.30 (q, J=7.5 Hz, 2 H) 2.40 (s, 3 H) 1.40 (d, J=8 Hz, 3 H) 1.31 (t, J=7.5 Hz, 3 H). [M+H] calc'd for C23H25N2O4S, 425; found, 425.
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4](C)[C:3]=1[CH2:10][OH:11].[H-].[Na+].I[CH2:15][C:16]([O-:18])=[O:17].[Na+]>C1COCC1>[CH2:10]([O:11][CH2:15][C:16]([OH:18])=[O:17])[C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])CI
Reactant: Cc1cc(C)c(CO)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COCc1ccccc1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
(2,4,6-Trimethyl-phenyl)-methanol (4.50 g, 30 mmol) was introduced to the suspension of sodium hydride (95%, 0.84 g, 35 mmol) in dry THF (100 ml), under a nitrogen blanket and the reaction mixture was heated to reflux for one hour. After the reaction mixture cooled down to 25° C., sodium iodoacetate (7.28 g, 35 mmol) was added in one portion, and the reaction was heated to reflux for another two hours. The resulting precipitate was collected by filtration, and then dissolved into water (60 ml). This aqueous solution was acidified to pH 2 at 5° C. by 6N HCl to generate precipitate, which was then isolated by filtration to give pure benzyloxy acetic acid as white powder (3.2 g, 51.2%), mp 81-83°. Microanalysis for C12H16O3 (208.26): C, 69.21, H, 7.74. found: C, 68.83, H, 7.66. 1H-NMR (d6-DMSO): 6.82 (s, 2 arom. H); 4.50 (s, OCH2CO2H); 4.01, 4.02 (2s, CH2O); 2.29 (s, 2 ortho-CH3); 2.20 (s, para-CH3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:23][C:22]([CH3:24])=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]=1[CH3:29])=O>>[CH3:24][C:22]1[NH:23][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:20]([CH3:29])[C:21]=1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c(C)c1CC(=O)O

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid (40 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].[F:15][C:16]1[C:21](I)=[CH:20][CH:19]=[CH:18][N:17]=1.CN(C)[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[F:15][C:16]1[C:21]([N:4]2[CH2:5][CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:2]([CH3:1])[C:3]2=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: Fc1ncccc1I
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1C(=O)N(c2cccnc2F)CC1C(=O)OC(C)(C)C
Yield: 68.6 %

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-fluoro-3-iodopyridine (352 mg, 1.998 mmol) in 1,4-dioxane (20 ml) was added trans-N,N-dimethylcyclohexane-1,2-diamine (0.062 ml, 0.400 mmol), potassium phosphate (1272 mg, 5.99 mmol) and copper(I) iodide (38.0 mg, 0.200 mmol) and the reaction mixture was heated at reflux under argon overnight. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated and washed with water (˜50 ml) containing 0.880 ammonia solution (˜5 ml), then brine and passed through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-80% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (405 mg, 67.3% yield). LC/MS [M+H]+=296. (ii) Trifluoroacetic acid (2 ml) was added to a solution of 1,1-dimethylethyl (4S)-1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.355 mmol) in dichloromethane (5 ml) and the solution was stirred at room temperature for 36 hours. The reaction mixture was reduced under vacuum and the residue was azeotroped with toluene and dried under heated vacuum to give 1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜1.35 mmol) which was used in the next step. LC/MS [M+H]+=240.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[SH:8].[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([CH2:28]Cl)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C.[I-].[K+]>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([CH2:28][S:8][C:4]3[S:3][CH:7]=[CH:6][CH:5]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Sc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3cccs3)c2CC1
Temperature: 45 °C
Reaction time: 13 h
Yield: 70.6 %

Procedure:
Suspend sodium hydride (20 mg, 60% dispersion in mineral oil) in anhydrous DMF (2 mL) and add thiophene-2-thiol (35 mg, 0.38 mmol) at room temperature. After 5 min add 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.38 mmol) and catalytic potassium iodide (1 mg) in anhydrous DMF (1 mL) and stir at 45° C. for 13 h. Cool the mixture to room temperature and partition between brine and EtOAc. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 7:3 gradient) to give 3-tert-butoxycarbonyl-7-chloro-6-(thiophen-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
Combine (5,6-dichloro-pyridin-3-yl)-methanol (3.05 g, 17.11 mmol) and manganese dioxide (37.2 g, 427.9 mmol) in CH2Cl2 (25 mL). Stir the reaction mixture at rt overnight. Filter the reaction mixture through Celite® washing with CH2Cl2 (2× 10 mL). Concentrate the filtrate and dry under vacuum to provide the title compound (1.44 g, 48%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=[CH:10][C:9]=2[C:8]([CH:20]=[CH2:21])=[CH:7]1>C(O)C.[Pd]>[CH2:20]([C:8]1[C:9]2[CH:10]=[N:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:14]=2[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=1)[CH3:21]
Reactant: C=Cc1cn(CCCOC)c2cc(C(=O)OCC)ncc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)c(CC)cn2CCCOC
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of ethyl 1-(3-methoxypropyl)-3-vinyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (460 mg) in ethanol (9 mL) was added 10% palladium on carbon (92 mg), and the mixture was stirred under hydrogen for 1 hour. An insoluble was filtered off, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1→1/1) to give ethyl 3-ethyl-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(106-2)] (294 mg) as a yellow oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12]C(OCC2C=CC=CC=2)=O)[C:9]([NH2:11])=[O:10])=[CH:3][CH:2]=1.[BrH:23]>C(O)(=O)C.CCOCC>[BrH:23].[NH2:12][C@H:8]([C:9]([NH2:11])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.08 h

Procedure:
6.55 g (22 mmoles) of Z--Phe--NH2, prepared as described in Example 1, Step 1, are dissolved in 13 ml of acetic acid, and 30 ml of 5 n hydrogen bromide in acetic acid are added to the solution. After 5 minutes of stirring a thick precipitate separates. The suspension is allowed to stand for one hour, thereafter it is diluted with dry ether and filtered. The crude product is dissolved in 240 ml of ethanol, the solution is decolorized, and the product is precipitated with 740 ml of ether. 4.90 g (91 %) of H--Phe--NH2.HBr are obtained; the white, crystalline substance is chromatographically uniform. (Two spots appear on the thin layer chromatogram: one of them belongs to the product and the other to hydrogen bromide). M.P.: 249-250° C., Rf8 : 0.50; Rf8,HBr: 0.35.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH:9]([CH2:10][O:11][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])=[O:18])=[CH:15][N:16]=2)[CH2:8]1.O1C(COC2SC(C(N)=O)=CN=2)C1>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([N:16]2[CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])=[O:18])[S:13][CH:12]2[O:11][CH2:10][CH:9]([OH:7])[CH3:8])[CH2:2][CH2:3]1
Reactant: CCC(C)CCCNC(=O)c1cnc(OCC2CO2)s1
Reactant: C1COCCN1
Agent: NC(=O)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: CCC(C)CCCNC(=O)C1=CN(N2CCOCC2)C(OCC(C)O)S1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I to the invention. In this example 1 g. of morpholine is added to a solution containing 0.3 g. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20° C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of the 1,2-epoxy-3-(5-aminocarbonylthiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1 -(N-morpholino-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography on silica gel.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:16])=O>>[C:1]12([C:11]([Cl:16])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-adamantanecarboxylic acid (0.27 g, 1.5 mmol) in 5 mL of thionyl chloride was warmed to reflux and stirred for 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 5 mL of toluene and concentrated under reduced pressure three times to afford the title compound, which was used without additional purification or characterization.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[N:11]=1.C(O)C>O>[O:20]([C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: O=C(O)c1ccco1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1ccco1
Temperature: 4 °C
Yield: 86.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-furancarboxylic acid (7.5 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (11.9 g). The product produced by precipitation in water (15.7 g; m.p. 164° C.) is dissolved in boiling ethanol (200 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-2-furancarboxamide (14.4 g) is produced, m.p. 167° C.