Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[N:31][OH:32])[CH2:29][CH3:30])=[CH:24][CH:23]=1.[C:33]([O:40][CH2:41][CH3:42])(=[O:39])[C:34]([O:36]CC)=O>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](=[N:31][OH:32])[CH:29]([CH3:30])[C:34](=[O:36])[C:33]([O:40][CH2:41][CH3:42])=[O:39])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=NO)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(=O)C(C)C(=NO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Diisopropylamine (18.2 mL, 129 mmol) was added to 60 mL of THF and cooled with an external ice bath. Butyllithium (50 mL, 126 mmol, 2.5 M in hexanes) was added and the mixture was stirred at 0° C. for 30 min, and brought to room temperature. The resulting LDA solution was added to a mixture of 1-(4-fluorophenyl)propan-1-one oxime (10 g, 59.9 mmol) and THF (50 mL) at 0° C. Following the addition, the reaction mixture was stirred at 0° C. for 1 hour and warmed to room temperature. The mixture was then transferred to a syringe and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (41 mL, 299 mmol) and THF (150 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 200 mL of 10% hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-35% EtOAc/hexanes) to give 10.1 g of the title compound. MS: (+) m/z 268.36 (M+1).
Reaction SMILES: CS([C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1)(=O)=O.[CH3:30][O-:31].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:31][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nnc(-c2ccc3ncn(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Reaction time: 2 h
Yield: 26.9 %

Procedure:
To a solution of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole (150 mg, 0.35 mmol) in N,N-dimethylformamide (3 mL) was added sodium methoxide (23 mg, 0.42 mmol) at room temperature, and the resulting mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (35.4 mg, yield 27%) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]=2[C:9]([CH3:29])=[CH:8][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:22]([N:11]1[C:10]2[C:9]([CH3:29])=[CH:8][CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][C:16]=2[C:19](=[O:21])[NH2:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)COc1ccc(C)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(OCC(=O)O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A slurry of 32 mg (0.0795 mmol) of [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl]oxyacetic acid methyl ester in 1 ml of tetrahydrofuran and 3.5 ml of methanol was treated with 0.3 ml of an aqueous 2 N sodium hydroxide solution and stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1:1 ethyl acetate/tetrahydrofuran and 0.2 N HCl solution. After another extraction with 1:1 ethyl acetate/tetrahydrofuran, the extracts were washed with brine, dried over magnesium sulfate and concentrated to afford (27 mg) of the title compound. mp. 253-254° C. ESIMS m/e 389 (M++1), 387 (M+−1) NMR (300 MHz, d6-DMSO): δ 12.83 (br, 1H); 7.75 (br, 1H); 7.53 (d, J=8.2, 1H); 7.41-7.34 (m, 2H); 7.28-7.17 (m, 3H); 7.07 (m, 2H); 6.90 (d, J=7.2, 2H); 6.49 (d, J=8.1, 1H); 5.89 (s, 2H); 4.79 (s, 2H); 2.52 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:27]=[CH:26][C:13]2[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:12]=2[CH:11]=1.C(OC1C=CC2CCNCCC=2C=1)C1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:27]=[CH:26][C:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:12]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(I)cc3F)cc2CC1
Agent: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Product: Fc1cc(I)ccc1Oc1ccc2c(c1)CCNCC2

Procedure:
The title compound was prepared from 1,1-dimethylethyl 7-[(2-fluoro-4-iodophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E274, Step 3) using an analogous method to that described for Description 2 (D2). MS (ES+) m/e 384 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:27][CH2:26][CH2:25][N:24]([C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[O:7])[CH2:23]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(C(F)(F)F)c3)C2)c1

Procedure:
The compound of Example 10 was prepared according to the general preparation protocol A from 3-trifluoromethylbenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [O-]CC.[Na+].[C:5]([CH:9]([C:15]([O:17]CC)=O)[C:10]([O:12]CC)=O)([CH3:8])([CH3:7])[CH3:6].[NH2:20][C:21]([NH2:23])=[O:22]>C(O)C>[C:5]([C:9]1[C:10](=[O:12])[NH:20][C:21](=[O:22])[NH:23][C:15]=1[OH:17])([CH3:6])([CH3:7])[CH3:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1c(O)[nH]c(=O)[nH]c1=O
Yield: 48.5 %

Procedure:
To a stirred solution of sodium ethoxide (prepared from 2.55 g of sodium, 10 mmol) in ethanol (60 ml), was added diethyl tert-butylmalonate (20 g, 92 mmol). The mixture was heated up to reflux. Urea (5.83 g, 97 mmol) in hot ethanol (50 ml) was added and the mixture was refluxed for 6 hr. The mixture was then evaporated in vacuo and the residue was dissolved in water (80 ml). The solution was washed with ether and the water layer was cooled in an ice bath and acidified by the addition of conc. hydrochloric acid. The precipitate was filtered, washed with cold water and n-hexane, and dried in vacuo to give 8.22 g (48%) of a white solid. m.p. 247-248° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.00 (9H, s), 2.83 (1H, s), 11.11 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2.[H-].[Na+].I[CH2:36][CH3:37]>CN(C)C=O>[CH2:36]([N:20]([C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:26]=1)[C:4]1[C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]=1[CH3:19])[CH3:37]
Reactant: CCI
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1cncc(N2CCOCC2)c1)c1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Reaction time: 2 h

Procedure:
To a stirred solution of 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine (0.06 g, 0.14 mmol) in N,N-dimethylformamide (1.4 mL) was added sodium hydride (0.011 g, 0.28 mmol) followed by iodoethane (0.043 g, 0.28 mmol). Stirring continued at 60° C. for 2 h. After which the reaction was quenched with water (25 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexane) to give the desired product N-ethyl-5,7-difluoro-3-methyl-N-(5-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.7 Hz), 7.83-7.96 (2H, m), 7.74 (2H, m), 7.34-7.50 (2H, m), 7.26 (1H, br. s), 6.93-7.04 (1H, m), 6.31 (1H, br s), 3.77-3.94 (5H, m), 3.70 (1H, m), 3.10 (4H, br. s), 2.33-2.40 (3H, s), 1.29 (3H, t, J=7.2 Hz). Mass Spectrum (ESI) m/e=462.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[N:15][NH:16]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[N:15][NH:16]3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(N)cc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
856 mg of zinc powder are added to 0.85 g of N-[6-(4-nitrophenyl)-1H-indazol-3-yl]butanamide, described in Example 64, in 50 cm3 of acetic acid, followed, one hour later, by addition of a further 856 mg of zinc, and the mixture is stirred for 1 hour at room temperature. The reaction medium is filtered through a sinter funnel packed with Celite and the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of tetrahydrofuran and 100 cm3 of ethyl acetate and the organic phase is washed successively with 100 cm3 of saturated sodium hydrogen carbonate solution and with 100 cm3 of saturated sodium chloride solution, then dried over magnesium sulphate, filtered and concentrated to dryness to give 500 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and the solid is triturated in 20 cm3 of diethyl ether, filtered off, washed with 2×5 cm3 of diethyl ether and then dried (90 Pa; 45° C.) to give 200 mg of N-[6-(4-aminophenyl)-1H-indazol-3-yl]butanamide in the form of yellow crystals melting at 230° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(O)(=O)=O>C1CCCCC1>[OH:17][C:11]1[CH:16]=[CH:15][C:14]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:7])=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CS(=O)(=O)O
Solvent: C1CCCCC1
Product: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 70 %

Procedure:
4-Hydroxy benzoic acid (13.8 g; 0.10 mole), phenol (10.3 g; 0.11 mole), 98% methane sulphonic acid (50 ml; 75.5 g; 0.8 mole) and cyclohexane (10 ml) were mixed and heated to reflux temperature. The solution was refluxed for 12 hours using a Dean and Stark apparatus (no sampling). The reaction mixture was worked up to give 4,4'-dihydroxy-benzophenone in 70% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C@@H:22]1([NH2:32])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1.[CH2:33]([N:36]([CH2:50][CH2:51][CH3:52])[C:37]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([CH2:48]C)[CH:47]=1)C(O)=O)=[O:38])[CH2:34][CH3:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[C:41]1[CH:45]=[C:46]([CH3:48])[CH:47]=[C:39]([C:37]([N:36]([CH2:33][CH2:34][CH3:35])[CH2:50][CH2:51][CH3:52])=[O:38])[CH:40]=1)[C@H:11]([OH:12])[CH2:13][NH:32][C@@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN[C@H]2CCCc3ccccc32)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3), (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+=592.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][C:5]1[CH:6]=[C:7]([C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[CH2:8]Cl>O.C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(Sc2ccccc2)c(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Sc2ccccc2)c(CC#N)c1

Procedure:
194 g of potassium cyanide in 250 ml of water are heated under reflux for 17 hours under an argon atmosphere with 616.9 g of 3-methyl-6-(phenylthio)-benzyl chloride in 900 ml of ethanol. Then the ethanol is distilled off under reduced pressure, the residue then diluted with water and extracted with ether. The extracts are washed with water, dried over sodium sulphate and evaporated. There is obtained 3-methyl-6-(phenylthio)-phenylacetonitrile as an oil.
Reaction SMILES: [C:1]([NH:11][C:12](=[N:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH3:30])=[O:27])[NH:18]C(OC(C)(C)C)=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[ClH:49].CCOC(C)=O>CCOC(C)=O>[ClH:49].[C:39]([NH:38][C:12](=[N:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:26]([NH:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)[CH3:30])=[O:27])[NH2:18])([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40]
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@H](N)CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-Nω,Nω '-bis(Cbz)-N2 -(Boc)-(R)-N-[1-(4-hydroxyphenyl)-ethyl]arginine amide (11.2 g; 16.4 mmol, from step (b) above) in EtOAc (300 mL) was treated with HCl/EtOAc (300 mL) and stirred overnight at room temperature. The product precipitated as a white residue from which the solvents were decanted. To the residue was added methanol (100 mL) followed by diethyl ether (50 mL). This mixture was slurried and then concentrated at reduced pressure to afford the sub-title compound as a white crushable foam (10.2 g; 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
A mixture of 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (100 mg, 0.26 mmol), tert-butyl 4-aminobenzoate (50 mg, 0.26 mmol), 1-methyl-1H-imidazole (85 mg, 1.02 mmol) and EDCI (200 mg, 1.02 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. Ethyl acetate (10 mL) and water (10 mL) were added to the mixture and the organic layer was washed with brine (10 mL×2) then dried over Na2SO4. The residue was concentrated and purified by chromatography (dichloromethane:MeOH=50:1) to give tert-butyl 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)benzoate (80 mg, 55%) as a yellow solid. LC-MS: [M+H]+, 567, tR=1.820 min
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19]([SH:22])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:26][C:27]([OH:29])=[O:28]>CN(C=O)C>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH2:26][C:27]([OH:29])=[O:28])=[N:18][CH:17]=2)[C:8](=[O:9])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCl
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cn1
Reaction time: 0.08 h

Procedure:
3-Cyclopentyl-2-(6-mercaptopyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 66, 50 mg, 150 μmol) was added to a stirred suspension of NaH (12 mg of a 60% dispersion in mineral oil, 300 μmol) in anhydrous DMF (0.8 mL). After 5 min, a solution of chloroacetic acid (14 mg, 150 μmol) in anhydrous DMF (0.4 mL) was added. The reaction was stirred for 15 min, then more NaH (10 mg of a 60% dispersion in mineral oil, 250 μmol) and chloroacetic acid (14 mg, 150 μmol) were added. After 15 min, the reaction mixture was partitioned between EtOAc (10 mL) and saturated aqueous Na2CO3—H2O (1:1, 15 mL). The aqueous phase was acidified to pH 2.5 with 2M HCl, then the resulting precipitate was extracted into EtOAc (15 mL). The EtOAc solution was washed with brine (5 mL), dried (MgSO4), filtered, concentrated, and recrystallised (CH2Cl2—IH) to give the title compound: RTA=3.52 min; m/z (ES+)=392.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution tert-butyl 2-[(3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]acetate, 2b, (0.12 g, 0.26 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. The crude residue was diluted with 5% MeOH/CH2Cl2 and the resulting white precipitate was filtered and washed with CH2Cl2 to afford the desired product, 577, as trifluoroacetic acid salt.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11].[C:12]([Cl:15])(Cl)=[O:13]>C1C=CC=CC=1>[CH3:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[N:3]([CH3:2])[C:12]([Cl:15])=[O:13]
Reactant: CNc1c(C)cccc1C
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N(C)C(=O)Cl

Procedure:
Into a suspension of 121.1 g. (0.71 moles) of N,2,6-trimethylaniline hydrochloride in 1 l. of benzene at reflux is bubbled an excess of phosgene (0.175 ml. of liquid or 1.6 moles). After introduction of the phosgene, the mixture is refluxed for 1 hour and then 700 ml. of benzene removed by distillation at slightly reduced pressure. After the phosgene is gone the residue is triturated with hexane (300 ml.), filtered and dried to give 2,6-dimethylphenyl-N-methylcarbamoyl chloride (m.p. 79°-80° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Product: Nc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
The title compound can be prepared by palladium catalyzed hydrogenation of 4-nitro-4′-biphenyl carboxylic acid.
Reaction SMILES: [C:1]([CH:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C@@H:7]([C:17]([OH:19])=[O:18])[NH:6][C:5]1=[O:20])(O)=O.N1CCCCC1.C=O.Cl>N1C=CC=CC=1>[CH2:1]=[C:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH2:8][C@@H:7]([C:17]([OH:19])=[O:18])[NH:6][C:5]1=[O:20]
Reactant: O=C(O)C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Agent: C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
(3R)-6-Carboxy-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid (1.71 g, 5.64 mmol) is dissolved in pyridine (20 ml) and piperidine (0.096 g, 1.13 mmol) is added followed by paraformaldehyde (0.25 g, 8.46 mmol). The mixture is heated to 65° C. and stirred for 2 hours. The mixture is cooled to room temperature, poured into 6N hydrochloric acid (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts are washed with brine (1×100 ml), dried (MgSO4) and solvent is evaporated to give (3R)-6-methylidene-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid, m.p. 184°-186° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[O:13]1CCOCC1>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: C1COCCO1
Product: O=Cc1ccc2cccc(O)c2n1
Temperature: 80 °C
Yield: 38 %

Procedure:
A solution of 8-hydroxy-2-methylquinoline (6.0 g, 37.7 mmol) in dioxane (15 ml) was added to a stirred solution of SeO2 (6.3 g, 56.8 mmol) in dioxane (80 ml) dropwise at 50° C. and the mixture was heated up to 80° C. for further 20 h. The resulting mixture was filtered. The filtrate was concentrated and the residue purified by column chromatography with Hex/EA=(15:1 to 10:1) to give 8-hydroxyquinoline-2-carboxaldehyde (2.45 g, 38%) derivatives as intermediates. Intermediate was converted into N-substituted compounds by reductive amination with aminoalcohol, aminoalkyne or other heterocycles to give series of compounds. 8-alkoxy-2-methyl quinoline were oxidized to give 8-alkoxyquinoline-2-carboxaldehyde derivatives and followed by the same method to give compounds M to O.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C(Cl)=CC=C(Cl)C=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8](=[O:13])[CH2:9][C:10]2([CH3:11])[CH3:12]
Reactant: CC(C)=CC(=O)c1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccc(Cl)cc1
Product: CC1(C)CC(=O)c2ccc(O)cc21
Temperature: 150 °C
Yield: 32 %

Procedure:
To a stirred solution of 1-(4-hydroxyphenyl)-3-methylbut-2-en-1-one (1.0 g, 5.67 mmol) in dichlorobenzene (50 mL) was added aluminum chloride (1.97 g, 14.74 mmol). The mixture was heated to 150° C. for 4 hours. After cooled to room temperature, the reaction mixture was poured over ice and extracted with dichloromethane (3×80 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) to give 5-hydroxy-3,3-dimethylindan-1-one as a tan solid (0.32 g, 32%). MS m/z 177.