Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH:10]([C:11]([OH:13])=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:23]1[CH:27]=[CH:26][NH:25][C:24]=1[CH2:28]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([S:7][CH:8]2[CH:10]([C:11]([O:13][CH2:28][C:24]3[NH:25][CH:26]=[CH:27][C:23]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC1(C)C(Sc2ccccc2)C1C(=O)O
Product: CC1(C)C(Sc2ccccc2)C1C(=O)OCc1[nH]ccc1Cc1ccccc1

Procedure:
Using the method of Example 1, 3-phenylthio-2,2-dimethylcyclopropanecarboxylic acid is reacted with 3-benzylpyrrolylmethyl alcohol to yield 3-benzylpyrrolylmethyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([N:16]=[C:17]=S)([CH3:15])[CH3:14]>C(OCC)(=O)C>[CH:13]([NH:16][C:17]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9](=[O:10])(=[O:11])[N:12]=1)([CH3:15])[CH3:14]
Reactant: CC(C)N=C=S
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)S(=O)(=O)N=C(NC(C)C)N2

Procedure:
The title compound was prepared from 2-amino-5-methylbenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 266-268° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.16 (d, 6H, CH(CH3)2), 3.91 (m, 1H, CH(CH3)2), 6.92 (br.d, 1H, NH), 7.06 (d, 1H, ArH), 7.35 (dd, 1H, ArH), 7.45 (d, 1H, ArH), 10.20 (br.s, 1H, NH); MS: m/e 253 (M+, 44%); (C11H15N3O2S1) calc. C, 52.16; H, 5.97; N, 16.59; found C, 52.28; H, 6.19; N, 16.49.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=2)=[N:5][C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].Cl.CN.C(Cl)CCl.[CH3:42][N:43]1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]1[C:4]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH:43][CH3:42])=[O:32])=[CH:28][CH:27]=2)=[N:5][C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(C#N)c(OCc3ccc(C(=O)O)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Reactant: CN1CCOCC1
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(COc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(C)cc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dried round bottom flask was added the product of Example 122 (0.030 g; 0.0613 mmol), methylamine hydrochloride (0.005 g; 0.0675 mmol), EDC (0.018 g; 0.0919 mmol), DMAP (0.007 g; 0.0613 mmol), N-methylmorpholine (0.028 mL; 0.251 mmol), and methylene chloride (0.5 mL). The reaction mixture was stirred at room temperature overnight. The volatiles were removed, and the residue was taken up in ethyl acetate, washed with saturated NaHCO3 (2×), water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-50% ethyl acetate:hexane) to afford the desired product: m/e=502 (M+1); Rt=4.2 min on LCMS. HPLC/MS: 502 (M+1); Rt=4.20 min
Reaction SMILES: [OH-].[K+].O.[C@@H:4]1([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]([O:28]CC)=[O:27])[C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]>CO>[C@@H:4]1([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]([OH:28])=[O:27])[C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CCOC(=O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Temperature: 50 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
A mixture of 24 g of potassium hydroxide, 80 ml of water, 240 ml of methanol, and 20 g (0.035 mol) of ethyl 7-β-galactosylcoumarin-3-carboxylate [Burd et al, Clin. Chem. 23, 1402 (1977)] was stirred at 50° C. for 15 hours. When cool, the methanol was removed under reduced pressure. The concentrated aqueous solution was acidified to pH 2 with concentrated hydrochloric acid. The precipitate was collected, washed with cold water, and recrystallized from hot water. The crystals were collected, washed with acetone, and dried at 80° C. for 1 hr. This gave 12 g (54% yield) of 7-β-galactosylcoumarin-3-carboxylic acid as white crystals, mp 250°-255° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([Br:16])=[CH:9][N:8]=1)C>C(O)(=O)C.[Fe]>[Br:16][C:10]1[CH:11]=[C:12]2[C:7]([O:6][CH2:5][C:4](=[O:3])[NH:13]2)=[N:8][CH:9]=1
Reactant: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1COc2ncc(Br)cc2N1
Temperature: 60 °C
Yield: 85.3 %

Procedure:
Iron powder (22.8 g, 408 mmol) was added to a solution of (5-bromo-3-nitropyridin-2-yloxy)-acetic acid ethyl ester (2.28 g, 7.47 mmol) in acetic acid (230 mL), and the reaction mixture was heated at 60° C. over 150 min, cooled to room temperature, and filtered. The filtrate was evaporated, taken up in dichloromethane/methanol 1:1 and neutralized with 1 M aq. sodium carbonate solution. The organic layer was washed with water and the aqueous layer re-extracted with dichloromethane. The combined organic layers were washed again with 1 M aq. sodium carbonate solution, dried (Na2SO4), and evaporated to produce 7-bromo-1H-4-oxa-1,5-diaza-naphthalen-2-one (1.46 g, 85%). Off-white solid, MS (ISP)=226.9 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1.[O:31]1[CH2:34][CH:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:18][N:15]1[C:14]([CH2:19][N:38]2[CH2:39][CH2:40][CH:35]([CH:33]3[CH2:34][O:31][CH2:32]3)[CH2:36][CH2:37]2)=[N:13][C:12]2[C:16]1=[N:17][C:9]([N:8]1[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=[C:4]1[CH2:3][CH2:2][OH:1])=[N:10][C:11]=2[N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21
Reactant: C1CC(C2COC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21
Reaction time: 18 h
Yield: 19.5 %

Procedure:
A solution of 2-[2-(2-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.49 mmol), 4-oxetan-3-ylpiperidine (83 mg, 0.59 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (5 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (156 mg, 0.74 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 97:3 to 95:5) to afford 512 as a white solid (51 mg, 20%). LCMS (Method I): RT=2.39 min, M+H+=533. 1H NMR (CDCl3, 400 MHz) δ 8.04 (m, 1 H); 7.75 (m, 1 H); 7.33 (m, 2 H); 4.76 (dd, J=7.8, 6.0 Hz, 2 H); 4.45 (t, J=6.0 Hz, 2 H); 4.35 (m, 4 H); 4.19 (t, J=5.5 Hz, 2 H); 3.94-3.80 (m, 9 H); 3.54 (t, J=5.5 Hz, 2 H); 3.02 (m, 2 H); 2.81-2.72 (m, 1 H); 2.29 (m, 2 H); 1.71 (m, 5 H) and 1.28 (m, 1 H)
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH2:5][OH:6].Cl.[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.O>[CH2:8]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:1][CH2:2][CH:3]=[CH:4][CH2:5][OH:6])=[O:30])=[CH:32][CH:33]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: OCC=CCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC=CCO)cc1
Reaction time: 4 h

Procedure:
To a mixture of 8.8 g. of 1,4-dihydroxy-2-butene and 2.84 g. of 4-dimethylaminopyridine is added 4.16 g. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride. The heat evolution is moderated with ice and stirring is continued for 4 hours. Chloroform and water are added and the chloroform extract chromatographed to remove any diacylated by-product. Evaporation to crystallization yields the 4-hydroxy-2-buten-1-yl 4-(n-hexadecylamino)benzoate as a white solid.
Reaction SMILES: CN(C)C(N1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([NH2:26])[C:20]=4[CH3:27])[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=O.ClC1C2C=C(C3CC[O:43]CC=3)NC=2N=CN=1>>[O:43]1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:27])=[C:21]([NH2:26])[CH:22]=[C:23]([F:25])[CH:24]=4)[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Reactant: Clc1ncnc2[nH]c(C3=CCOCC3)cc12
Product: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Intermediate 12 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with Intermediate 11.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[H-].[Na+].[C:14](Cl)(=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.CCOC(C)=O>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)Nc1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6-aminoisoquinoline in DMF cooled to 0° C. was added NaH and the solution was stirred for 30 minutes at 0° C. Then hydrocinnamoyl chloride was added and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with EtOAc, extracted with NaHCO3(sat), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 10% hexanes/EtOAc) gave N-(isoquilin-6-yl)-3-phenylpropanamide (E2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6](N)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.N(OS(=O)(=O)O)=[O:15]>C(Cl)Cl.O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:15])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1C(N)=O
Reactant: O=NOS(=O)(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc(Br)cc(C)c1C(=O)O
Reaction time: 2 h
Yield: 96 %

Procedure:
4-Bromo-2-methoxy-6-methylbenzamide (2.0 g, 8.2 mmol), dissolved in CH2Cl2, was added dropwise to nitrosyl sulfuric acid (14.0 mL) in water (6.0 mL) at 0° C. and stirred for 2 hours. The reaction mixture was poured over ice and extracted with CH2Cl2, and the solvent was removed under reduced pressure to afford a light pink solid (1.93 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.07 (s, 1H), 7.00 (s, 1H), 3.93 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][C:4](=[O:6])[C:3]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=2[OH:1])[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: NC1CC1
Product: COc1ccc(C(=O)NC2CC2)c(O)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A suspension of methyl 2-hydroxy-4-methoxybenzoate (5.1 g, 28.0 mmol) in cyclopropyl amine 24 mL) was stirred at room temperature for 5 days. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-60% ethyl acetate in petroleum ether) to give the subtitled compound (1.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:16]([CH3:15])[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)c1ccc2cc(O)ccc2c1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and N-methylbenzylamine (commercially available) according to the procedure described for Example A. MS (m/e): 290.1 (MH−, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH:10]=[O:11].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=2[CH:10]=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCCCCCc1ccccc1
Reactant: O=Cc1ccc(O)c(C=O)c1
Product: O=Cc1ccc(OCCCCCCc2ccccc2)c(C=O)c1

Procedure:
4-(6-phenylhexyloxy)-1,3-benzenedicarboxaldehyde was prepared from 4-hydroxy-1,3-benzenedicarboxaldehyde and 6-phenylhexyl chloride using the method in Example 1 at a higher reaction temperature of 140° C.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[CH:18]([CH3:19])[N:17]([CH:20]([F:22])[F:21])[C:16](=[O:23])[CH2:15][NH:14]2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[F:1][C:2]1[C:12]([N:13]2[CH:18]([CH3:19])[N:17]([CH:20]([F:21])[F:22])[C:16](=[O:23])[CH2:15][NH:14]2)=[C:11]([N+:24]([O-:26])=[O:25])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC1N(c2cc3c(cc2F)OCC(=O)N3)NCC(=O)N1C(F)F
Solvent: CC(=O)O
Product: CC1N(c2c(F)cc3c(c2[N+](=O)[O-])NC(=O)CO3)NCC(=O)N1C(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[7-Fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4-difluoromethyl-3-methyl-1,4-dihydro-1,2,4-triazin-5-one (0.38 g) was dissolved in acetic acid (10 ml) and fuming nitric acid (10 ml) was added slowly at ambient temperature. The resulting mixture was stirred for 1 hour and poured into ice-water. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluted with ethyl acetate and hexanes (1:3) to give title compound (0.17 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[CH2:16][C@H:15]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].[Br:36]Br.[OH-].[Na+]>C(O)(=O)C>[Br:36][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:17]2[C:12]=1[CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:30])[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16]2
Reactant: BrBr
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Br)c3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
(R)-N-[8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide (80 mg, 0.19 mmol) and sodium acetate (200 mg) were dissolved in acetic acid (3 mL) and the mixture was stirred at room temperature. Bromine (34 mg, 0.21 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 2 h at ambient temperature. A 2 M sodium hydroxide solution (100 mL) was added and the mixture was extracted with diethyl ether (2×50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification on a silica gel column using methylene chloride/ethanol saturated with NH3 (94:6) as the eluent gave 80 mg (85% yield) of the title compound as a white solid: mp 229-230° C.; [α]21D−5.4° (c=1, chloroform); EIMS (70 eV) m/z (relative intensity) 495 and 497 (3, M+).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19](Br)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:31]4[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N(C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ncccc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)C)C3)nn12
Temperature: 150 °C
Yield: 87.4 %

Procedure:
A mixture of [(S)-1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid isopropyl ester (88 mg, 0.23 mmol), 2-methoxypyridine-3-boronic acid (46 mg, 0.3 mmol), K2CO3 (95 mg, 0.69 mmol) and dichlorobis(triphenylphosphine)palladium(II) (8.4 mg, 0.012 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (82.5 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.06 Hz, 6H) 2.13-2.32 (m, 2H) 2.89 (s, 3H) 3.43 (dd, J=10.48, 6.95 Hz, 1H) 3.48-3.56 (m, 1H) 3.69-3.76 (m, 2H) 4.09 (s, 3H) 4.99 (dt, J=12.38, 6.19 Hz, 2H) 6.62 (d, J=9.85 Hz, 1H) 7.04 (dd, J=7.45, 4.93 Hz, 1H) 7.79 (d, J=9.85 Hz, 1H) 8.13-8.19 (m, 2H) 8.86 (dd, J=7.71, 1.64 Hz, 1H). LRMS (ESI) m/z 411.2 [(M+H)]+, calc'd for C21H26N6O3: 410.48.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[N:12]=[C:13]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[C:14]([C:19]([NH2:21])=[O:20])=[N:15][C:16]=1[CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[NH2:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:11]1[N:12]=[C:13]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)[C:14]([C:19]([NH2:21])=[O:20])=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Reactant: Nc1cccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of 3-amino-2-fluorophenol (50 mg), 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (162 mg), potassium carbonate (65 mg), and N-methylpyrrolidone (1 mL) was stirred at 100° C. for 2 hours. To the reaction mixture was added water-saturated brine (1:1), followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-(3-amino-2-fluorophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (126 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:36]2([C:41]([F:44])([F:43])[F:42])[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:30][C:31]([O:33]CC)=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:36]2([C:41]([F:43])([F:44])[F:42])[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:30][C:31]([OH:33])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C(F)(F)F)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1(C(F)(F)F)CCCC1
Temperature: 25 °C

Procedure:
To a solution of racemic ethyl 3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-(trifluoromethyl)cyclopentyl)propanoate, 197a, (0.080 g, 0.120 mmol) in THF (10 mL) was added lithium hydroxide (2 mL of 2N solution). The reaction was refluxed for 3 hours and cooled to room temperature. The non aqueous solvent was removed under reduced pressure and the aqueous layer was adjusted to pH 4. The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic phases concentrated in vacuo to afford 16 mg of the desired product as a pale yellow solid: 1H NMR (300 MHz, d6-DMSO) δ 8.51 (s, H), 8.25-7.97 (m, 2H), 7.58-7.42 (m, 2H), 7.12 (d, J=7.5 Hz, H), 4.35 (m, H), 2.85 (m, 2H) and 1.27-0.70 (m, 8H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.55 minutes (M+H) 456.45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)c(F)c(Cl)c1

Procedure:
3,5-dichloro-4-fluorobenzoic acid was refluxed with >1 equivalent of thionyl chloride and one drop of DMF neat or as a solution in CHCl3. The solvent and volatile by-products were removed in vacuo to provide 3,5-dichloro-4-fluorbenzoyl chloride.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]4([C:34]([NH:36][C:37]5[CH:42]=[CH:41][C:40](/[CH:43]=[CH:44]/[C:45]([O:47]CC)=[O:46])=[CH:39][CH:38]=5)=[O:35])[CH2:33][CH2:32][CH2:31]4)=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]4([C:34]([NH:36][C:37]5[CH:42]=[CH:41][C:40](/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46])=[CH:39][CH:38]=5)=[O:35])[CH2:31][CH2:32][CH2:33]4)=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)c3ccc4c(C5CCCCC5)c5n(c4c3)CCOc3cc(OC)ccc3-5)CCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC3(C(=O)Nc4ccc(/C=C/C(=O)O)cc4)CCC3)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.1 %

Procedure:
To a solution of ethyl (E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylate (102 mg, 0.154 mmol) in tetrahydrofuran (3 ml) and methanol (2 ml), was added 2N aqueous sodium hydroxide solution (1.2 ml), and the mixture was stirred at room temperature for 17 hr. 2N Hydrochloric acid (1.3 ml) was added and the mixture was extracted with ethyl acetat. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane:diethyl ether (1:1) solution was added to the obtained residue, and the precipitated solid was collected by filtration and washed with hexane:diethyl ether (1:1) solution. The obtained solid was dried in vacuo to give (E)-3-[4-({1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]cyclobutanecarbonyl}amino)phenyl]acrylic acid (84 mg, yield 86%).