Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:10].[CH:11](I)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[C:3]([O:10][CH:11]([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1cccc(C=O)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C=O)c1OC(C)C

Procedure:
Stir a mixture of 3-methylsalicylaldehyde (100 g, 0.73 mol), isopropyl iodide (187 g, 1.1 mol) and K2CO3 (141 g, 1.0 mol) in DMF (400 mL) for 20 hr at room temperature. TLC shows partial reaction; thus, add more isopropyl iodide (43 g, 0.25 mol) and heat the reaction to 45° C. with stirring for an additional 10 hr. Dilute the reaction mixture with H2O (1 L) and extract the resulting mixture with EtOAc. Wash the organic layer with 0.25 M. aqueous NaOH and then with H2O. Dry over MgSO4 and evaporate the solvent to give 3-methyl-2-isopropoxybenzaldehyde, 122 g (94%); 1H-NMR (CDCl3) δ 7.7-7.1 (m, 3H), 4.2 (m, 1H), 2.3 (s, 3H), 1.4 (d. 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][NH:14][CH:15]=O)[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]2[C:4]=1[CH:15]=[N:14][CH2:13][CH2:12]2
Reactant: COc1cc(CCNC=O)cc2c1OCO2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c2c(cc3c1OCO3)CCN=C2
Temperature: 100 °C
Yield: 97.5 %

Procedure:
2.23 g (10 mmol) of N-[2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl]formamide (C) was dissolved in 25.5 ml of methylene chloride, and to this mixture was added 1.87 ml (20 mmol) of phosphorus oxychloride. The resulting mixture was refluxed under heating for 7 hours and concentrated under reduced pressure. The residue was added with 50 ml of toluene and 50 ml of water, then further added with 14 ml of 20% sodium hydroxide aqueous solution, stirred under heating at 100° C. for one hour and cooled. The reaction mixture was separated and the aqueous layer was extracted with 25 ml of toluene. The toluene layers were combined, washed with 25 ml of water and dried over anhydrous magnesium sulfate. Distillation off the solvent gave 2.00 g of 8-methoxy-6,7-methylenedioxy-3,4-dihydroisoquinoline (D) (yield: 98%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([N+]([O-])=O)=[C:11](/[CH:18]=[CH:19]/[N:20](C)C)[N:10]=[C:9]1/[N:23]=[CH:24]/[N:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[NH:20][CH:19]=[CH:18][C:11]=2[N:10]=[C:9]1/[N:23]=[CH:24]/[N:25]([CH3:26])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/c1nc(/N=C/N(C)C)n(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)/C=N/c1nc2cc[nH]c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of (E)-N′-(1-benzyl-4-((E)-2-(dimethylamino)vinyl)-5-nitro-6-oxo-1,6-dihydropyrimidin-2-yl)-N,N-dimethylformimidamide (43.0 g, 0.12 mol) in THF (151 mL) was added an aqueous saturated solution of Na2S2O4 and stirred at room temperature overnight. Upon completion of the reaction, the solid was filtered and washed with THF to afford the product (21.2 g, 62% yield) which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:38]=[CH:37][C:15]3[C:16]4[C:20]([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)=[CH:19][N:18]([C:24]2[N:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[N:26]=[CH:27][N:28]=2)[N:17]=4)[CH2:9]1)=O)(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[NH:8]1[CH2:9][CH:10]([C:12]2[CH:38]=[CH:37][C:15]3[C:16]4[C:20]([CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)=[CH:19][N:18]([C:24]2[N:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[N:26]=[CH:27][N:28]=2)[N:17]=4)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.11 mmol) was dissolved in hydrochloric acid in dioxane (10 mL, 4N) and the reaction stirred at RT for 1 h. After approximately 5 min a thick white precipitate formed. The reaction was concentrated in vacuo to yield 8-Azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride as a yellow solid (1.0 g, 100%). LCMS: RT=3.00 min, M+H+=421.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]([CH3:57])=[N:44][N:45]([C:47]4[N:52]=[C:51]([C:53](O)=[O:54])[C:50]([CH3:56])=[CH:49][N:48]=4)[CH:46]=3)=[O:41])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]([CH3:57])=[N:44][N:45]([C:47]4[N:52]=[C:51]([C:53]([N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)=[O:54])[C:50]([CH3:56])=[CH:49][N:48]=4)[CH:46]=3)=[O:41])[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2
Reactant: C1COCCN1
Reactant: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C(=O)N1CCOCC1
Reaction time: 8 h

Procedure:
BOP (88 mg, 8 mmol) is added to a solution of 2-{4-[(adamantan-1-ylmethyl)-carbamoyl]-3-methyl-pyrazol-1-yl}-5-methyl-pyrimidine-4-carboxylic acid (41 mg, 0.1 mmol), morpholine (13 mg, 0.15 mmol) and DIEA (39 mg, 0.3 mmol) in DCM (3 mL). The solution is stirred overnight, evaporated and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer is washed with brine, dried and evaporated. Purification by PTLC, eluting with a mixture of 5% MeOH and 1% TEA in DCM, affords the title compound. 1H NMR (CDCl3): 8.80 (s, 1H), 8.65 (s, 1H), 5.93 (s, 1H), 3.81 (s, 4H), 3.63-3.66 (m, 1H), 3.46 (s, 1H), 3.29 (t, 1H), 3.10-3.15 (m, 2H), 2.85-2.90 (m, 1H), 2.58 (s, 3H), 2.31 (s, 3H), 1.99 (s, 3H), 1.53-1.73 (m, 12H). MS (M+1)=479.37; RT=1.30 min. *IC50.
Reaction SMILES: C([O-])=O.[Na+].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[C:17]([NH:19][CH2:20][C:21]([CH3:23])=[CH2:22])[C:16](I)=[CH:15][N:14]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][NH:19][C:17]=2[CH:18]=1
Reactant: C=C(C)CNc1cc(Cl)ncc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)CNc2cc(Cl)ncc21
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Palladium (II) acetate (300 mg, 1.34 mmol), sodium formate (2.40 g, 30.53 mmol), tetra-n-butyl-ammonium chloride (8.48 g, 30.53 mmol) and triethylamine (10.6 mL, 76.32 mmol) were added to a solution of (2-chloro-5-iodo-pyridin-4-yl)-(2-methyl-allyl)-amine (7.85 g, 25.44 mmol) in toluene (200 mL) and water (10 mL) and the mixture was stirred and held at 100° C. under a nitrogen atmosphere overnight. The mixture was filtered whilst hot and the solids rinsed with toluene (50 mL), water (50 mL) and EtOAc (50 mL). The organic solvent was removed in vacuo, the aqueous residues were diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The organic layer was separated, the solvent was removed in vacuo and the residues subjected to column chromatography on silica. Elution with 30-100% EtOAc in petrol afforded the title compound (4.12 g, 89%) as a colourless solid. 1H NMR (DMSO-d6) 7.72 (1H, s), 6.75 (1H, br s), 6.33 (1H, s), 3.32 (2H, d), 1.25 (6H, s). MS: [M+H]+ 183.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[OH:24][CH2:25][C@@H:26]1[CH2:30][NH:29][CH2:28][C@H:27]1[OH:31]>>[Br:1][C:2]1[C:3]([N:29]2[CH2:30][C@H:26]([CH2:25][OH:24])[C@@H:27]([OH:31])[CH2:28]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OC[C@@H]1CNC[C@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](CO)[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 6.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2) and trans-4-(hydroxymethyl)pyrrolidin-3-ol hydrochloride to afford an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=476.2/478.2 [M+H]+, m/z=474.0/476.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.11-2.23 (m, 1H) 3.25-3.34 (m, 2H) 3.39-3.49 (m, 1H) 3.50-3.62 (m, 2H) 3.83-3.96 (m, 2H) 4.04-4.12 (m, 1H) 4.70 (t, J=5.27 Hz, 1H) 5.07 (d, J=4.37 Hz, 1H) 7.33 (d, J=8.75 Hz, 2H) 7.83 (d, J=9.00 Hz, 2H) 8.32 (d, J=2.06 Hz, 1H) 8.66 (d, J=1.80 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]([O:9]C)=O)[C:5](=O)[CH2:4][O:3]1.[CH:12]([NH2:14])=[NH:13].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][CH:2]1[C:6]2[C:7]([OH:9])=[N:14][CH:12]=[N:13][C:5]=2[CH2:4][O:3]1
Reactant: N=CN
Reactant: COC(=O)C1C(=O)COC1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1OCc2ncnc(O)c21
Temperature: 25 °C

Procedure:
A mixture of methyl 2-methyl-4-oxotetrahydrofuran-3-carboxylate (8.3 g, 52.8 mmol), formamidine (7.0 g, 68.6 mmol) and toluene (200 mL) was heated to reflux under Dean-Stark conditions overnight. The mixture was allowed to cool to room temperature, diluted with water and neutralized by the addition of saturated Na2CO3. The organic layer was separated and the aqueous layer extracted with EtOAc (5×200 mL). The combined organic layers were dried with brine, MgSO4 and concentrated. The residue was purified by column chromatography (100% EtOAc to 5% MeOH:EtOAc) to give 5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol as a brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.58 (s, 1H), 8.18 (s, 1H), 5.18 (bs, 1H), 4.82 (d, J=14.4 Hz, 1H), 4.72 (d, J=14.4 Hz, 1H), 1.37 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6]O)=[C:4]([F:11])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][Br:32])=[C:4]([F:11])[CH:3]=1
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(F)c1CBr
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 4 g (17.6 mmol) 4-bromo-2,6-difluorobenzyl alcohol in 50 ml THF, 7 g (26.4 mmol) triphenylphosphine and 8.83 g (26.4 mmol) carbon tetrabromide are added with stirring. Stirring is continued for 10 min at 0° C. and for 1 h at room temperature. After that the reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane) to afford the title compound as yellowish oil.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([NH:19][C:20](=S)[NH:21][NH:22][C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[O:24])=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=C(C(NC(=S)NNC(C3SC=CC=3)=O)=O)C3C(=CC=C(OC(F)(F)F)C=3)N=2)C=CC=CC=1>>[O:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[C:23]1[O:24][C:20]([NH:19][C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=2)=[O:18])=[N:21][N:22]=1
Reactant: O=C(NC(=S)NNC(=O)C1CCCO1)c1cc(-c2ccccc2)nc2ccccc12
Agent: O=C(NNC(=S)NC(=O)c1cc(-c2ccccc2)nc2ccc(OC(F)(F)F)cc12)c1cccs1
Product: O=C(Nc1nnc(C2CCCO2)o1)c1cc(-c2ccccc2)nc2ccccc12

Procedure:
The title compound was synthesized according to the synthesis method of the compound Ia-122 using 4-(2-phenyl-4-quinolinecarbonyl)-1-(2-tetrahydrofurancarbonyl)thiosemicarbazide described in Reference Example 38 instead of 4-(2-phenyl-6-trifluoromethoxy-4-quinolinecarbonyl)-1-(2-thiophenecarbonyl)thiosemicarbazide.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:39]([N:41]([CH2:50][CH3:51])[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:40].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:31])=[O:30])[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([N:47]1[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][N:41]([CH2:50][CH3:51])[CH2:39][CH3:40])[CH2:45][CH2:46]1)=[O:6]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Reactant: CCN(CC)CCN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)CCN1CCN(C(=O)c2cc(-c3cnc4c(c3)c(-c3ccccc3OC)cn4S(=O)(=O)c3ccc(C)cc3)cc(F)c2N)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.3 %

Procedure:
300 mg (0.564 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid, 105 mg (0.564 mmol) of 1-(2-diethylaminoethyl)piperazine, and 279 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) were combined in 3.5 mL dimethyl formamide and stirred at room temperature for 48 hours. The reaction was extracted into ethyl acetate and washed with water. The water layer was back extracted three times with ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions containing the purified intermediate were evaporated to afford 230 mg (0.329 mmol, 58% yield) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone as a white solid. 1H NMR (500 MHz, CD3CN) δ 8.59 (d, 1H), 8.09 (s, 1H), 8.09 (d, 2H), 8.01 (s, 1H), 7.61 (dd, 1H), 7.43 (m, 4H), 7.23 (d, 1H), 7.18 (d, 1H), 7.11 (t, 1H), 4.67 (s, 2H), 3.88 (s, 3H), 3.60 (s, br., 4H), 2.52 (m, 12H), 0.99 (t, 6H); MS: m/z 699.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([C:28](O)=[O:29])=[CH:25][C:24]=2[CH:31]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:28]([C:26]3[O:27][C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:31][C:24]=4[CH:25]=3)=[O:29])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cc3cc(Cl)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.1 %

Procedure:
To a solution of N1-(4-methoxybenzoyl)-1,2-benzenediamine (200 mg, 0.826 mmol) in methylene chloride (5 mL) was added 5-chlorobenzofuran-2-carboxylic acid (162 mg, 0.826 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (316 mg, 1.65 mmol), and 4-dimethylaminopyridine (10 mg, 0.083 mmol). The resulting solution was stirred at room temperature for 6 h. The resulting precipitate was collected via vacuum filtration to provide 209 mg (60%) of the title compound as an amorphous off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:22])[CH2:17][CH2:16]2)[N:3]=1.[CH3:35][O-:36].[Na+]>>[CH3:35][O:36][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:22])[CH2:17][CH2:16]2)[N:3]=1
Reactant: CN1CCN(c2nc(Cl)nc(N3CCC(C(=O)NCc4ccccc4C(F)(F)F)CC3)n2)CC1
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1
Temperature: 80 °C
Yield: 4.6 %

Procedure:
⅕ of the suspension prepared in step b of Example 20 (0.542 mmol, 1.00 equiv) was concentrated under reduced pressure. Then, sodium methoxide (1.24 mL of 25 wt % solution in MeOH, 5.42 mmol, 10.0 equiv) was added. The resulting mixture was heated to 80° C. for 1 h. The final solution was purified by reverse-phase HPLC (Sunfire, 20-40% CH3CN, H2O, 0.1% TFA, 12 min) to afford 12.2 mg of the title compound. MS (ES+): m/e 493.8 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nccc(N)n1
Solvent: O=CO
Product: CCOC(=O)c1nccc(NC=O)n1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of formic acid (100 g) and acetic anhydride (204 g) was stirred for half an hour at ambient temperature. To the solution was added ethyl 4-aminopyrimidine-2-carboxylate (30 g) and the mixture was stirred for 1.5 hours at 70° to 75° C. and then evaporated to dryness. The residue was triturated with ethanol, collected by filtration and washed with ethanol to give ethyl 4-formamidopyrimidine-2-carboxylate (20.0 g), mp 205°-206° C.
Reaction SMILES: [CH:1]1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCC[CH2:2]1.[Cl:35][C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:47])=[CH:43][C:44]=2[F:46])[N:39]=[C:38]([C:48]2[CH:53]=[C:52](Cl)[CH:51]=[CH:50][N:49]=2)[C:37]=1[CH3:55].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:35][C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:47])=[CH:43][C:44]=2[F:46])[N:39]=[C:38]([C:48]2[CH:53]=[C:52]([CH:1]=[CH2:2])[CH:51]=[CH:50][N:49]=2)[C:37]=1[CH3:55]
Reactant: Cc1c(-c2cc(Cl)ccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Temperature: 100 °C
Reaction time: 76 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.049 mmol), 4-chloro-2-(4-chloropyridin-2-yl)-5,7-difluoro-3-methylquinoline (0.10 g, 0.31 mmol), vinyl boronic acid MIDA ester (0.056 g, 0.31 mmol) and Pd2dba3 (0.011 g, 0.012 mmol) in toluene (3.1 mL) was added sodium tert-butoxide (0.074 g, 0.77 mmol). The reaction mixture was heated to 100° C. and stirring continued for 76 h. The crude product was purified by column chromatography on silica gel (0 to 50% hexanes/EtOAc) to give the desired product 4-chloro-5,7-difluoro-3-methyl-2-(4-vinylpyridin-2-yl)quinoline. Mass Spectrum (ESI) m/e=317.0 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.I[CH2:30][CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[CH2:30]([O:28][C:26]1[CH:25]=[CH:24][C:23]2[N:19]([CH2:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:20]=[N:21][C:22]=2[CH:27]=1)[CH3:31]
Reactant: CCI
Reactant: Oc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.4 %

Procedure:
A mixture of 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (80 mg, 0.20 mmol) from Example 147, iodoethane (47 mg, 0.30 mmol) and Cs2CO3 (196 mg, 0.6 mmol) in NMP (3.5 mL) was stirred at rt for 5 h. The mixture was added to water and extracted with DCM. The organic layer was separated, washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to afford (1R,2R)-2-((6-((5-ethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (35 mg, 42%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.14-7.19 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 5.41 (s, 2H), 4.72 (d, J=4.8 Hz, 1H), 3.97-4.04 (m, 2H), 3.43-3.54 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.60-1.65 (br m, 2H), 1.32 (t, J=13.8 Hz, 3H), 1.15-1.24 (m, 4H). LCMS (ESI) m/z 423 (M+H)+.
Reaction SMILES: C(OC([NH:6][CH:7]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]([CH2:24][C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[C:8]1=[O:31])=O)C.Cl>C(Cl)Cl>[NH2:6][CH:7]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]([CH2:24][C:25]([C:27]([CH3:29])([CH3:28])[CH3:30])=[O:26])[C:8]1=[O:31]
Reactant: CCOC(=O)NC1N=C(c2ccccn2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)CN1C(=O)C(N)N=C(c2ccccn2)c2ccccc21
Reaction time: 50 h
Yield: 93.3 %

Procedure:
A solution of (3RS)-ethoxycarbonylamino-1-(tert-butylcarbonylmethyl)-2,3-dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (10.0 g, 23.7 mmol) in DCM (40 ml) was added to the above solution below 25° C. and the mixture was stirred for 50 h. The mixture was then poured into 3M HCl (80 ml) below 25° C. and the aqueous portion was washed with DCM (10 ml×2). The combined organic portions were extracted with 3M HCl (20 ml). DCM (50 ml) was added to the combined aqueous portions and the mixture was basified to pH 10 with 25% NaOH below 5° C. The organic portion was washed with brine (50 ml) and evaporated. CH3CN (50 ml) was added and the mixture was filtered to remove the small amount of insoluble material. The filtrate was evaporated to give the rifle compound as a brown foam (7.75 g, 93%), which was not purified further.
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([OH:15])=[O:14].O>C(O)C>[OH:11][CH:10]1[CH2:9][CH2:8][C@H:7]([CH2:12][C:13]([OH:15])=[O:14])[C@H:6]1[CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH3:1]
Reactant: CC/C=C\CC1C(=O)CCC1CC(=O)O
Solvent: O
Solvent: CCO
Product: CC/C=C\C[C@H]1C(O)CC[C@@H]1CC(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In a 50 ml three-necked flask equipped with a refrigerant, a thermometer and a magnetic stirring device, 1 g (4.8 mmol) of (+/−)-jasmonic acid (b) was dissolved in 15 ml of absolute ethanol. 430 mg (11.4 mmol) of sodium borohydride NaBH4 was added. The mixture was stirred for 4 hours at 50° C. Once the reaction had ended, 5 ml of water was slowly added. The precipitate formed was filtered off. The filtrate was acidified to a pH=5 with hydrochloric acid and was then extracted with ethyl acetate (3×30 ml). The organic phase was dried over sodium sulphate, filtered through filter paper, and then concentrated. The colorless oil obtained was purified by silica gel chromatography (eluent: dichloromethane/methanol). The colorless oil obtained was dried under vacuum.