Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1.C1(C(O)=O)C2C(=CC=CC=2)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O-]C1C=CC=CC=1>C1(C)C=CC=CC=1.[OH-].[Na+].C(OCC)(=O)C>[CH3:11][O:10][C:8]1[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:1][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:9]=1
Reactant: Cc1cccc(Br)n1
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(Oc2cccc(C)n2)c(C=O)cc1-c1cccs1
Temperature: 110 °C
Yield: 65.9 %

Procedure:
Ex-122A: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (0.68 g, 2.9 mmol) and 2-bromo-6-methylpyridine (0.25 g, 1.4 mmol) in toluene (1.0 mL) was added ethyl acetate (0.0063 g, 0.072 mmol, 1-naphthoic acid (0.50 g, 2.9 mmol), 5 Å molecular sieves (0.36 g), cesium carbonate (0.94 g, 2.9 mmol), and copper(I) triflate-benzene complex (0.020 g, 0.036 mmol). The phenoxide crashed out of solution upon addition of cesium carbonate and additional toluene (1 mL) was added to facilitate stirring. The heterogeneous solution was immediately heated to 110° C. and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with a 5% sodium hydroxide solution (10 mL) and ethyl acetate (10 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (5×20 mL). The combined organic extracts were washed with a 50% brine solution (1×25 mL), brine (1×25 mL), dried over sodium sulfate and concentrated to an dark brown semi-solid. Silica gel chromatography (ethyl acetate/hexanes, 1:4) afforded 0.30 g (65%) of 4-methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehyde as a light orange solid, mp 140–141° C. 1H-NMR (300 MHz, CDCl3) δ 10.21 (s, 1H), 8.23 (s, 1H), 7.64 (dd, 1H, J=7.8, 7.2 Hz), 7.52 (d, 1H, J=3.3 Hz), 7.35 (d, 1H, J=5.1 Hz), 7.10 (dd, 1H, J=5.1, 3.3 Hz), 6.94 (d, 1H, J=7.2 Hz), 6.78 (d, 1H, J=7.8 Hz), 6.75 (s, 1H), 3.92 (s, 3H), 2.44 (s, 3H). HRMS (EI) Calcd. for C18H15NO3S: 325.0773. Found: 325.0775. Anal. Calcd. C18H15NO3S: C, 66.44; H, 4.65; N, 4.30; S, 9.85. Found: C, 60.00; H, 4.58; N, 4.05; S, 9.84.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[N:7]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:6]=[C:5]([CH3:17])[C:4]=1[CH2:18]O.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[OH:38][CH2:39][CH:40]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][NH:41]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C.O.C(#N)C.CN(C)C=O>[CH3:1][N:2]([CH3:20])[C:3]1[N:7]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:6]=[C:5]([CH3:17])[C:4]=1[CH2:18][N:41]1[CH:40]([CH2:39][OH:38])[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1
Reactant: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N(C)C)c1CO
Reactant: OCC1Cc2ccccc2CN1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N(C)C)c1CN1Cc2ccccc2CC1CO
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To an ice-bath-chilled, well-stirred solution of the compound of Step C (160 mg, 0.48 mmol and triethylamine (0.08 ml, 0.60 mmol) in anhydrous methylene chloride (3 ml), methanesulfonyl chloride (0.04 ml, 59.2 mg, 0.52 mmol) was added all at once. After 15 minutes of stirring at 5° C. to complete in situ formation of the mesylate of the compound of Step C, the dextrorotatory enantiomer of 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (310 mg, 1.9 mmol), anhydrous N,N-dimethylformamide (0.51 ml) and acetonitrile (1.2 ml) were added. After stirring 1/2 hour at ambient temperature, the reaction mixture was heated at 55° C. for 19 hours. Concentration in vacuo afforded an orange residue which was dissolved in ethyl acetate/water (100 ml of each) with the pH adjusted to 10 with sodium carbonate. The separated aqueous phase was extracted twice with 50 ml portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to an orange semi-solid (0.7 g). Flash chromatography of the entire sample (silica gel, 40 micron mesh; eluting with ethyl acetate/hexane=1.3 volume) afforded the title compound (170 mg) as a light-orange oil. 13C NMR (CDCl3): 151.6, 151.0, 136.2, 135.3, 135.0, 133.6, 133.3, 129.0, 128.6, 127.0, 126.5, 126.1, 107.5, 62.0, 58.0, 47.6, 45.6, 42.6, 26.2, 13.1.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15].C(NCC)C>C1C=CC=CC=1.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>[OH:16][CH2:13][C:14]#[C:15][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCNCC
Product: CCOC(=O)c1ccc(C#CCO)cc1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
2.5 g of tetrakis(triphenylphosphine)palladium (0) was added to 50 ml of a solution of 10 g of ethyl p-bromobenzoate in benzene at room temperture. The obtained mixture was stirred at that temperature for one hour, followed by the addition thereto of 2.5 g of propargyl alcohol, 0.84 g of cuprous iodide and 19 g of diethylamine. The obtained mixture was stirred at room temperature for 26 hours and filtered through Celite. Water (50 ml) was added to the filtrate and the obtained mixture was extracted with ethyl acetate. The organic phase was washed with a 10% aqueous solution of hydrochloric acid and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 20% ethyl acetate/n-hexane) to give 3.1 g of the title compound as a pale-yellow solid.
Reaction SMILES: C(OC([C:6](=[C:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH3:21])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O)C.C(=O)=O.[OH-].[Na+]>Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[CH3:21])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=C1CCCCCN1C)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Product: CN1CCCCCC1Cc1ccc(Cl)cc1
Yield: 36.7 %

Procedure:
Boil 15.5 g of 2-(α-ethoxycarbonyl-4-chlorobenzylidene)- 1-methylperhydroazepine and 110 ml of concentrated hydrochloric acid under reflux until the evolution of CO2 ceases. Cool the resulting reaction mixture to ambient temperature; then alkalize it with caustic soda solution (while cooling with ice) and extract the product with diethyl ether. Concentrate the ether phase and dry the prepared concentrate over sodium sulfate. Dissolve the residual 2-(4-chlorobenzylidene)-1-methylperhydroazepine (7.44 g) in ethyl alcohol and hydrogenate with platinum/active carbon/hydrogen. Filter the catalyst from the hydrogenated product, distil off the solvent and then distil the remainder under a high vacuum to obtain 4.4 g of the title compound with a BP of 102° to 110° at 0.003 mm of Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Br:10]Br>C(Cl)(Cl)(Cl)Cl.II>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([Br:10])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc[nH]1
Reactant: BrBr
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
A solution of pyrrole-2-carboxylic acid methyl ester (79.9 mmol, 10.0 g) in carbon tetrachloride (300 ml) was heated to 70° C., then treated dropwise with a solution of bromine (99.9 mmol, 126.0 ml) in carbon tetrachloride (200 ml). The reaction was initiated by the addition of iodine (40 mg). After the addition was complete, the reaction was held at 70° C. for 10 min, then cooled to room temperature using an ice bath. The mixture was washed with 10% aqueous sodium carbonate (100 ml), followed by water (100 ml). The organics were concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 4.5 g (27%) of 5-bromo-1H-pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) δ 9.29 (1H, s), 6.80 (1H, dd, J=3.9, 2.7), 6.23 (1H, dd, J=3.8, 2.6), 3.88 (3H, s).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[N:29]=[C:28]([N:30]2[CH2:34][CH2:33][C:32]([CH3:36])([OH:35])[CH2:31]2)[C:27]([F:37])=[C:26]([NH:38][NH2:39])[N:25]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:24]1[N:25]=[C:26]([NH:38][NH:39][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:37])=[C:28]([N:30]2[CH2:34][CH2:33][C:32]([OH:35])([CH3:36])[CH2:31]2)[N:29]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CC1(O)CCN(c2nc(Cl)nc(NN)c2F)C1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(O)CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)C1

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.122 g, 0.4 mmol), racemic 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-3-methyl-3-pyrrolidinol (0.104 g, 0.4 mmol), NMM (0.13 mL, 1.2 mmol), HOAt (0.054 g, 0.4 mmol), EDC (0.077 g, 0.4 mmol) and DMF (2 mL) were combined. When the reaction was complete, the mixture was purified by RP-HPLC to provide [(2R)-3-{2-[2-chloro-5-fluoro-6-(3-hydroxy-3-methyl-1-pyrrolidinyl)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide as a mixture of diastereomers (0.035 g, 16%). LCMS: (M+H)+=549.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([CH2:28][C:29]([O:31]C)=O)=[N:9]1.[CH2:33]([NH2:35])[CH3:34].Cl.C(N)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([CH2:28][C:29]([NH:35][CH2:33][CH3:34])=[O:31])=[N:9]1
Reactant: COC(=O)Cc1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)Cc1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of the methyl [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]acetate (100 mg, 0.2 mmol), EtNH2 (2.0M in THF, 5 mL) and ethylamine hydrochloride (200 mg) was stirred at 70° C. in a sealed vial for 8 h. The solvent was removed in vacuo, another EtNH2/THF (2.0M, 5 mL) was added, the mixture was stirred at 78° C. for another 24 h. Another 3 mL of EtNH2/THF was added, and the mixture was stirred at 78° C. for another 20 h. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (0-30% 20% MeOH/DCM) to give the title compound as a white solid (85 mg, 83%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.84-7.82 (m, 1H), 7.74-7.71 (m, 1H), 7.60-7.46 (m, 5H), 7.21 (d, 1H), 6.78 (d, 1H), 6.61 (s, 1H), 6.45 (brs, 1H), 3.69 (s, 2H), 3.30 (q, 2H), 3.07 (s, 3H), 1.14 (t, 3H). MS(ES): 500 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:22][C:3]2[CH:4]=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]3=[O:21])[C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[N:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: Clc1nccc(OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nccc(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
2.6 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 1.7 g of 4-benzyloxy-2-chloropyrimidine were dissolved in 20 ml of N,N-dimethylformamide, to this solution was added 1.07 g of potassium carbonate, and the mixture was stirred for 2 hours at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 1.6 g of 4-benzyloxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine.
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]=[C:11]([C:25]([F:28])([F:27])[F:26])[N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=23)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:29]>O1CCOCC1>[ClH:29].[O:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]2[N:10]=[C:11]([C:25]([F:27])([F:28])[F:26])[N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=23)=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1nc(C(F)(F)F)n2c1CNCC2)N1CCOCC1
Reaction time: 12 h

Procedure:
Tert-butyl 1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 20b (470 mg, 1.27 mmol) was dissolved in 20 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain crude morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone hydrochloride 20c (300 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)(=[O:37])=[O:36].FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:44][CH:41]4[CH2:42][CH2:43][N:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NC2CCN(S(C)(=O)=O)CC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 43 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92, triethylamine (0.1 mL, 0.818 mmol), and 1-(methylsulfonyl)-4-piperidinamine as the trifluoroacetic acid salt (171 mg, 0.589 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-[-(methylsulfonyl)-4-piperidinyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 43% yield), as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.33 (d, J=7.6 Hz, 1 H), 8.58 (s, 1 H), 7.41 (s, 1 H), 7.18-7.14 (m, 2 H), 7.05-7.00 (m, 2 H), 4.14-4.09 (m, 3 H), 3.75-3.69 (m, 2 H), 3.58 (s, 3 H), 2.97 (m, 2 H), 2.82 (s, 3 H), 2.14 (m, 2 H), 1.76 (m, 2 H); HRMS m/z calcd for C23H26FN4O5S: 489.1602. Found: 489.1609.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[N:4]=1.[OH-].[Na+].O1CC[CH2:29][CH2:28]1>C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[N:4]=[C:3]([C:2]3[N:1]=[C:28]([CH3:29])[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: C1CCOC1
Reactant: CC(C)(C)CCC(=O)N1CCN(c2nccc(C(N)=NO)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccnc(N3CCN(C(=O)CCC(C)(C)C)CC3)n2)no1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyrimidin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (186 mg) obtained in Example 64-1) was dissolved in tetrahydrofuran (3 mL), and oily sodium hydroxide (25 mg) was added thereto and stirred at 60° C. for 20 minutes. Then, ethyl acetate (0.082 ml) was added to it and heated under reflux for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=19/1) to obtain 53.4 mg of the entitled compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C@@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11][N:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([NH:32][CH3:33])[N:24]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[Ni]>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C@@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11][N:10]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH:32][CH3:33])[N:24]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1nc(N2CC[C@H](c3cc(F)c(F)cc3F)[C@@H](NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(N2CC[C@H](c3cc(F)c(F)cc3F)[C@@H](NC(=O)OC(C)(C)C)C2)ccc1N
Temperature: 40 °C

Procedure:
To a stirring solution of 68 mg (0.14 mmol) of the product of Step B in 8 mL of 10:1 tetrahydrofuran/methanol under nitrogen was added 0.20 mL Raney Nickel (slurry in water). The resulting mixture under hydrogen was heated at 40° C. for 1 h and then cooled to ambient temperature over 24 h. The mixture was then filtered through a pad of Celite and the filter cake washed with dichloromethane and methanol. The combined filtrate and washings were concentrated in vacuo and the resulting purple solid was purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 10-90% acetonitrile/water with 0.1% trifluoroacetic acid) to afford the title compound as a purple crystalline solid. LC/MS 452.5 (M+1).
Reaction SMILES: [C:1]([C:9]1[N:10](C(OCC)=O)[C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:15][CH:14]=[C:13]([Cl:23])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][NH:31][CH3:32].O>CN(C=O)C>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:22])[CH2:20][N:31]([CH3:32])[CH3:30])=[CH:15][CH:14]=[C:13]([Cl:23])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(=O)CCl)c2ccc(Cl)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A mixture of 2-benzoyl-6-chloro-3-(chloroacetylamino)-1-(ethoxycarbonyl)indole (step 1, 890 mg, 2.12 mmol) and dimethylamine hydrochloride (520 mg, 6.36 mmol) in DMF (30 ml) was stirred for 2 h. Water (80 ml) was added and the mixture extracted with an ethyl acetate-toluene mixture (2:1 v/v, 30 ml×2). The combined organic extracts were washed consecutively with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated. The residue was treated with a solution of 1N aqueous KOH (20 ml) and EtOH (40 ml) for 1 h, volatiles removed by evaporation and the residue extracted with ethyl acetate (30 ml×2). The combined organic extracts were dried (MgSO4) and evaporated. The crude product was recrystallized from ethyl acetate/hexane to give 350 mg (47%) of the title compound as a yellow solid. m.p.: 175-176° C. 1H-NMR (CDCl3) δ: 10.60 (1H, br s), 8.83 (1H, br s), 8.08 (1H, d, J=8.8 Hz), 7.88-7.70 (2H, m), 7.68-7.42 (3H, m), 7.29 (1H, d, J=1.8 Hz), 7.07 (1H, dd, J=1.8, 8.8 Hz), 3.04 (2H, s), 2.33 (6H, s)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]#[N:19])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(C)(C)C.Cl>ClCCl.C(O)(C)C>[ClH:27].[NH2:7][CH:8]1[CH:9]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[CH:14][C:15]=2[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C(Cc1ccc(Cl)cc1)C(N)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl[1-(4-chlorobenzyl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (15 mg, 0.038 mmol) was dissolved in dichloromethane (1.5 mL) and 5 M hydrochloric acid in isopropanol (0.3 mL) was added. The reaction mixture was stirred for 3 h at room temperature. The solvent and the excess hydrochloric acid were evaporated in vacuo. Yield: 11 mg (0.033 mmol, 87%, colorless solid).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1.[Cl:25]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2[Cl:25])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(Cl)n2n1

Procedure:
A stirred mixture of 2-[4-(2-methoxyethoxy)phenyl]-6-propoxyimidazo[1,2-b] pyridazine (164 mg, 0.50 mmol), N-chlorosuccinimide (67 mg, 29.4 mmol) and chloroform (3 mL) was heated under reflux for 1.5 hours. The mixture was cooled and washed with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was purified by radial chromatography on silica gel. Elution with 0-2% methanol in dichloromethane afforded Compound 91 (158 mg, 87%) as an off-white solid. 1H n.m.r. (CDCl3) δ 1.07, t, J=7.5 Hz, 3H; 1.75-2.0, m, 2H; 3.47, s, 3H; 3.78, t, J=4 Hz, 2H; 4.19, t, J=4 Hz, 2 H; 4.38, t, J=6.5 Hz, 2H; 6.74, d, J=9.5 Hz, 1H; 7.04, d, J=8.5 Hz, 2H; 7.81, d, J=9.5 Hz, 1H; 8.06, d, J=8.5 Hz, 2H. Mass spectrum (APCI+) m/z 362/364 (M+H, 100%).
Reaction SMILES: [CH:1]1([CH:5]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=4)[NH:21][CH:20]=3)[N:13]=2)[CH2:6][C:7]([O:9]C)=[O:8])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO.[NH4+].[Cl-].CCOC(C)=O>[CH:1]1([CH:5]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=4)[NH:21][CH:20]=3)[N:13]=2)[CH2:6][C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1CCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1CCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a racemic solution of methyl 3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)propanoate (0.042 g, 0.109 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added NaOH (0.300 mL of 2 M solution, 0.600 mmol) and the reaction mixture was warmed to 50° C. After stirring the reaction mixture for 1 hour, the mixture was diluted with aqueous saturated NH4Cl solution and EtOAc. The organic layer was dried (MgSO4), filtered and evaporated to dryness to afford 36 mg of the desired product that was used without further purification: 1H NMR (400 MHz, d6-DMSO) δ 12.26 (s, 2H), 8.55 (d, J=9.7 Hz, 1H), 8.19 (dd, J=45.1, 15.8 Hz, 3H), 7.48 (d, J=8.1 Hz, 1H), 4.79 (s, 1H), 2.58 (dd, J=20.6, 12.2 Hz, 2H), 1.85 (ddd, J=29.4, 26.5, 21.1 Hz, 7H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.10 minutes (M+H) 374.02.