Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[Cl:50]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:50][C:3]1[C:4](=[O:49])[N:5]([CH2:46][CH2:47][CH3:48])[C:6](=[O:45])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:2]=1[Cl:1]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c(Cl)c(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Yield: 34.9 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g) and N-chlorosuccinimide (0.14 g) in chloroform (10 ml) was heated under reflux for 18 hours. The reaction mixture concentrated to dryness and the resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.22 g, 35%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH:10]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([F:36])[CH:31]=2)[CH2:11][C:12](=O)[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:7][CH:8]=1.[NH2:40][NH2:41].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO>[F:38][C:2]([F:39])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:40]=[N:41][C:12]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:18]3)=[CH:11][C:10]=2[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([F:36])[CH:31]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(F)c1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccnc(F)c3)c(-c3cccc(C(F)(F)F)c3)nn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
Under Ar, a solution of 19 (8.8 g, 14.1 mmol) in EtOH (270 mL) was stirred at room temperature and treated with hydrazine (1.4 g, 42.1 mmol). After 2 h, the reaction was concentrated to dryness. The reaction was partitioned between H2O and EtOAc (3×). The organic extracts were backwashed with brine, dried, filtered and concentrated to dryness. The residue was dissolved in toluene (400 mL) and treated with DDQ (3.4 g, 14.9 mmol). After stirring at room temperature for 3 h, the reaction was concentrated to dryness. The residue was chromatographed on a Still column (100 mm) and the product eluted with 60% EtOAc-hexanes to yield 5.5 g of 20.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]1([CH3:20])[CH2:19][O:18]1)(=[O:12])[CH3:11].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:20][C:17]([OH:18])([CH3:19])[CH2:16][CH2:15][CH2:14][O:13][C:10](=[O:12])[CH3:11])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(=O)OCCCC1(C)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OCCCC(C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 79.1 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (6.8 g, 43 mmol), 2-(3-acetoxypropyl)-2-methyloxirane (5.8 g, 39.3 mmol) and sodium acetate (3.9 g, 47.6 mmol) were suspended in ethanol (60 ml) followed by stirring under reflux overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to afford 2-chloro-l-(5-acetoxy-2-hydroxy-2-methylpentyl)-4-nitroimidazole (9.5 g, yield 79%) as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][CH:11]=1
Reactant: CCc1c(N)cccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(N)cccc1CO
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of methyl 3-amino-2-ethylbenzoate (0.83 g, 4.63 mmol), in THF (40 ml) was added Lithium aluminium hydride (0.9 g, 23.7 mmol). The mixture was heated at 50 C. for 5 h, cooled to 0 C. and hydrolysed cautiously with water. The slurry was extracted with EtOAc (×5). The extracts were washed with brine, dried Na2SO4, and evaporated. The residue was purified by chromatography (CH2Cl2/MeOH) to give the title compound 0.63 g (89%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([NH:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:6].[CH3:19][O:20][C:21](OC)(OC)OC>>[CH2:9]([CH:8]([NH:7][C:5]([C:4]1[CH:15]=[CH:16][C:17]2[O:18][C:19]([O:20][CH3:21])=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Reactant: COC(OC)(OC)OC
Product: CCCC(CCC)NC(=O)c1ccc2oc(OC)nc2c1
Yield: 60 %

Procedure:
Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 4aa) and tetramethylorthocarbonate. Yield: 60%. mp 137-138° C.; MS (M+H, 291.10).
Reaction SMILES: ClC1C=CC(C([N:8]([C:10](=[O:27])[C@H:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=2[CH3:26])[C:12]([OH:15])([CH3:14])[CH3:13])[NH2:9])=O)=CC=1.CCN(P1(N(C)CCCN1C)=N[C:37]([CH3:40])([CH3:39])[CH3:38])CC>C1COCC1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([NH:16][C@@H:11]([C:10]2[O:27][C:40]([C:37]3[CH:38]=[CH:20][C:19]([Cl:25])=[CH:18][CH:39]=3)=[N:9][N:8]=2)[C:12]([OH:15])([CH3:13])[CH3:14])[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: Cc1c(N[C@@H](C(=O)N(N)C(=O)c2ccc(Cl)cc2)C(C)(C)O)ccc(C#N)c1Cl
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Cl)cc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 669.2 %

Procedure:
The crude material of (R)-4-chloro-N-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)benzohydrazide (intermediate 15a) (230 mg, 0.53 mmol) was added to THF (50 mL) stirred at room temperature. PS-BEMP (721 mg, 1.59 mmol base) was added to the solution followed by slow addition of p-TSCl (111 mg, 0.58 mmol). The reaction mixture was stirred for 1 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to provide the product (740 mg): 1H NMR (500 MHz, CDCl3, δ in ppm) 7.95 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 7.39 (d, J=9 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 5.37 (d, J=9 Hz, 1H), 4.74 (d, J=9 Hz, 1H), 2.36 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.O.NN>O1CCCC1>[CH3:1][C:2]1[C:3]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2ccccc2)n1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C)c(C(=NOCc2cccc(N)n2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
To a solution of 2-{6-[({[(3,6-dimethylpyrazin-2-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (4.08 g, 8.80 mmol) in tetrahydrofuran (60 mL) was added dropwise hydrazine hydrate (2.14 mL, 44.0 mmol). After stirring at room temperature for 6 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the combined filtrates concentrated in vacuo, diluted in ethyl acetate (100 mL), washed with water (70 mL), dried over MgSO4 and concentrated to dryness in vacuo. Purification on silica gel afforded 6-[({[(3,6-dimethylpyrazin-2-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine [1.97 g, yield 64%; HPLC/MS: m/z=334 (M+H); log P(HCOOH)=1.31].
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C:7]2[C:18]3[C:17](=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=3)[NH:20][C:8]=2[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccc(Cl)cc1
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Product: Cc1[nH]c2ccc(F)cc2c1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Chloro-phenoxy)-propan-2-one (2.05 g) was added to a stirred solution of (4-fluoro-phenyl)-hydrazine (1.4 g) in ethanol (30 ml) at RT. After 2 h, the solvent was removed under reduced pressure and the residue dissolved in DCM (30 ml). Phosphorus trichloride (1.06 ml) was added dropwise to the solution and after stirring at RT for 16 h the reaction was quenched with aq. sodium hydrogencarbonate solution. The mixture was extracted with DCM, the organics washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 20% ethylacetate/iso-hexane. Yield 0.75 g
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[H-].[Na+].Br[CH2:11][Cl:12]>CN(C)C=O.O>[Cl:12][CH2:11][S:7][C:4]1[S:3][C:2]([CH3:1])=[N:6][N:5]=1
Reactant: ClCBr
Reactant: Cc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(SCCl)s1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of 2-methyl-1,3,4-thiadiazole-5-thiol (2.64 g: 20 mMol.) in dimethylformamide (40 ml) is added under ice cooling sodium hydride (880 mg: 60% dispersion in oil: 1.1 equivalents: 22 mMol.) in portions, and the mixture is stirred for 10 minutes. To the resulting solution is added bromochloromethane (40 ml), and the mixture is stirred at the same temperature for another 1 hour and 30 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and purified by silica gel chromatography (toluene: ethyl acetate=10:1) to give 5-chloromethylthio-2-methyl-1,3,4-thiadiazole (3.3 g) as colorless oil. Yield: 91%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH2:11].[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17]>C(OCC)C>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:11][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])=[O:17]
Reactant: CC1Cc2ccccc2C1N
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: CC1Cc2ccccc2C1NC(=O)NCCCl
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred mixture of 0.9 gram (0.0061 mole) of 2-methylindanylamine (known compound) in 20 mL of diethyl ether was added 0.53 gram (0.0062 mole) of 2-chloroethyl isocyanate. The reaction mixture was stirred for one hour at which time it was filtered. The filter cake was rinsed with diethyl ether, then was dried under reduced pressure to yield 1.2 grams of [(2-chloro-ethyl)amino]-N-(2-methylindanyl)carboxamide as a solid, melting point 105-106° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.[C:20]([OH:43])(=O)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:59][C@@H:60]([C:63]([OH:65])=[O:64])[CH2:61][OH:62].C(N(CC)CC)C>C(#N)C.O>[C:20]([NH:59][C@@H:60]([C:63]([OH:65])=[O:64])[CH2:61][OH:62])(=[O:43])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: N[C@H](CO)C(=O)O
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)N[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
4-hydroxyphenyldimethylsulfomethyl sulfate (trade name: SANCELER-DSP, manufactured by Sanshin Kagaku Kogyo Co., Ltd.) 2.66 g (0.01 mol) was heated and dissolved in 40 ml of acetonitrile. Docosahexaenoic acid 3.28 g (0.01 mol) was added to the solution obtained in a stream of nitrogen, and stirred at 0° C. To the mixture solution, dicyclohexyl carbodiimide 2.06 g (0.01 mol) was added little by little, and the solution was stirred for 2 hours at 0° C. and then for 2 hours at room temperature. The solution reacted was filtered to remove dicyclohexyl urea, and the filtrate was distilled in vacuo to obtain oily residue. D-serine 1.05 g (0.01 mol) and triethyl amine 1.4 ml (0.01 mol) were added to 10 ml of water. An acetonitrile solution of the above oily residue was added to the mixture with stirring, and stirred for 10 hours at room temperature. After reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was adjusted to pH 2 or 3 with 6N-HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium acetate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-docosahexaenoyl-D-serine 1.7 g was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.1 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (59 mg, 44%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([CH:13]=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[CH3:16][O:17][NH2:18]>N1C=CC=CC=1>[CH3:16][O:17][N:18]=[CH:13][C:10]1[CH:11]=[CH:12][N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: CON
Reactant: O=Cc1ccn(-c2ncccc2Cl)n1
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1ccn(-c2ncccc2Cl)n1
Yield: 97.8 %

Procedure:
A mixture of 2.00 g of 1-(3-chloro-2-pyridinyl)-1H-pyrazole-3-carbaldehyde, 1.21 g of O-methylhydroxylamine hydrochloride and 8 ml of pyridine was heated to reflux for 1 hour. After the reaction mixture was concentrated under reduced pressure, an aqueous saturated sodium hydrogen carbonate solution was poured into the residue and the mixture was extracted with methyl t-butyl ether three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.23 g of 1-(3-chloro-2-pyridinyl)-1H-pyrazole-3-carbaldehyde O-methyloxime of the formula:
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH3:25])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:32])=[N:4][CH:5]=1)[CH3:25]
Reactant: C[C@@H](Nc1cnc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: C[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)propanamide (97 mg, 0.430 mmol), 6-aminoquinoline (62 mg, 0.430 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg). The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg, 0.045 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (14 mg). MS 352.58 (M+H); UV 202.9, 265.2, 297.2, 357.9 nm; t 0.335 min.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[NH:23][CH2:22][CH2:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=3[CH:28]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[CH2:29]([O:31][CH2:32][CH2:33][CH:34]=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][N:23]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=3)=[CH:28][C:18]=2[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]1)[CH3:30]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CCOCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOCC)cc1
Reaction time: 20 h
Yield: 96.9 %

Procedure:
To a solution of methyl 7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (400 mg) and 3-ethoxypropionaldehyde (0.53 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.66 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction system was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:3) to give methyl 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (475 mg) as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](I)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[CH:43]([C:45]1[CH:46]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:47]3[CH:48]=[N:49][CH:50]=[C:45]([CH:43]=[O:44])[CH:46]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3cncc(C=O)c3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (250 mg) is dissolved in N,N-dimethylformamide (2 ml), then thereto are added 5-formylpyridin-3-boronic acid pinacol ester (164 mg), tetrakis(triphenylphosphine)palladium (81 mg) and sodium carbonate (90 mg), and the mixture is stirred at 100° C. overnight under nitrogen flow. After allowing to cool to room temperature, a saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-formylpyridin-3-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (119 mg). MS (m/z): 689 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([O:20]C)=[O:19])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.CO.O.[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=[O:19])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: COC(=O)c1nn(C)c(=O)cc1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
Methyl 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (84.9 mg, 0.211 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (2.5 mL) and water (2.5 mL). Aqueous 2 M lithium hydroxide (200 μL) was added at room temperature. After 10 minutes, the reaction mixture was heated to 50° C. for 30 minutes and continued to stir at room temperature for 16 hours at which time the solvents were evaporated. The residue was made acidic with 2 M aqueous hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic layer separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (54.0 mg, 66% yield). MS (EI) for C12H9N3O3FI: 390 (MH+).