Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([NH2:42])[CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([NH:42][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:40][CH3:41]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CCC(N)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 1-(2-pyridyl)-propylamine (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 65 mg of the title compound.
Reaction SMILES: [NH2:1][C:2](=O)[C@H:3]([NH:5][C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:4]>C1COCC1>[NH2:1][CH2:2][C@H:3]([NH:5][C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:4]
Reactant: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Solvent: C1CCOC1
Product: C[C@H](CN)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 47 %

Procedure:
To a solution of the product from example 9, step (a) (6.9 g) in THF (100 ml) was added borane-methylsulfide complex (4.4 ml) and the mixture heated under reflux for 2 hours. The mixture was carefully quenched by the addition of methanol (100 ml), evaporated to dryness and the residue taken up into methanol (100 ml) and acidified to pH 1-2 with concentrated hydrochloric acid. Heated under reflux for 30 mins then evaporated to dryness. The residue was triturated with ether to give a solid, which was collected by filtration, dissolved in water and the free base precipitated by the addition of aqueous sodium bicarbonate solution to give the subtitle compound (3.1 g).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]=[CH:9][N:8](COC(=O)C(C)(C)C)[C:7]2=[O:30]>C(O)C.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]=[CH:9][NH:8][C:7]2=[O:30]
Reactant: COCCOCCOc1cc2ncn(COC(=O)C(C)(C)C)c(=O)c2cc1OC
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: COCCOCCOc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
Saturated methanolic ammonia (20 ml) was added to a solution of 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.26 g, 5.5 mmol) in a mixture of ethanol (40 ml) and methylene chloride (15 ml). The mixture was stirred for 24 hours at ambient temperature, and further methanolic ammonia (20 ml) was added. The mixture was stirred for a further 24 hours at ambient temperature and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, dried under vacuum to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3,4-dihydroquinazolin-4-one (975 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)cc1F
Temperature: 40 °C
Yield: 87.4 %

Procedure:
To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.0 g, 18.7 mmol) in DMF (80 mL) and H2O (8 mL) was added KCN (1.21 g, 18.7 mmol). The mixture was heated to 40° C. for 3 hours before it was cooled down to room temperature. The reaction was diluted with H2O (40 mL) and extracted with Et2O (3×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash column chromatography (0-15% EtOAc in hexanes) to give the product (3.5 g, 87% yield). 1H NMR (300 MHz, CDCl3) δ: 3.72 (s, 2H), 7.26-7.35 (m, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.[Br:19]([O-])(=O)=O.[K+]>>[Br:19][C:10]1[CH:9]=[C:8]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc(CC(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
4′-isobutylacetophenone (215 g) was added to 49% sulfuric acid (1 Liter) was and potassium bromate (268 g) was added under ice-cooling over 1.5 h. The mixture was warmed to room temperature and stirred further for 1 h, which was followed by extraction with toluene. The organic layer was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The remaining oily substance was distilled under highly reduced pressure to give 3′-bromo-4′-isobutylacetophenone (182 g), boiling point: 130–140° C./0.15 mmHg
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.S(Cl)([Cl:15])=O.CN(C=O)C>C1(C)C=CC=CC=1>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([Cl:15])=[O:12])[CH:7]=[CH:6][C:5]=12
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2nonc2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2nonc2c1
Yield: 79.8 %

Procedure:
In a 500 ml reactor fitted with mechanical stirring, thermometer, addition funnel, reflux condenser and nitrogen inlet, [2,1,3]-benzoxadiazole-5-carboxylic acid (28 g) was suspended in toluene (245 ml). To this suspension was added thionyl chloride (39.4 g) and DMF (0.35 ml). The resulting mixture was heated to reflux and maintained for 3 hours. A short pass column was installed and toluene was distilled (atmospheric pressure, 124 ml) off to remove excess reagent. After cooling the remaining toluene was distilled off, which resulted in a thick oil. This oil was distilled (90° C., 2 mm Hg) to remove impurities and the product crystallized on standing (79.8% yield), mp: 55-58° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>N1C=CC=CC=1.Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)CC)cc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 15.3 %

Procedure:
To a cold solution (0° C.) of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)-methyl]phenoxy}acetate (38 mg, 0.086 mmol) in anhydrous pyridine (2 mL) was added ethanesulfonyl chloride (Fluka, 40 ∞l, 0.43 mmol) and the reaction mixture was stirred at 0° C. for 4 hrs and at rt for an additional 15 hours. The reaction mixture was diluted with an aqueous solution of HCl (1N) and extracted with DCM (3×). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (cHex/EtOAc) gave 7 mg (15%) of the title compound as a colorless oil. LC/MS, M+(ESI): 534.3 (purity: 94.5%).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C(O[K])(C)(C)C.C1(C)C=CC=CC=1>CC(O)(C)C>[C:1]([NH:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)NC(C)=O
Temperature: 85 °C
Reaction time: 17 h
Yield: 52.5 %

Procedure:
Into a 100-mL stainless-steel autoclave was put 143 mg (1 mmol) of methyl 2-acetamido-2-propenate, 22.6 mg [0.03 mmol (Cu reduced)] of [CuBr((S)-SEGPHOS)]n and 33.6 mg (0.3 mmol) of tBuOK, followed by replacing with nitrogen in the autoclave, and then 1.4 mL of a mixed solvent of toluene and t-BuOH in a ratio of 3:1 was added. The reaction was carried out with stirring under a hydrogen pressure of 3.0 MPa at 85° C. for 17 hours to give methyl 2-acetamidopropionate, which is a hydrogenated compound of methyl 2-acetamido-2-propenate in a yield of 52.5%.
Reaction SMILES: Cl.[CH:2]1([NH:5][CH:6]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:16]C)[O:8][CH2:7]2)[CH2:4][CH2:3]1.B(Br)(Br)Br.N>C(Cl)Cl>[CH:2]1([NH:5][CH:6]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[OH:16])[O:8][CH2:7]2)[CH2:4][CH2:3]1
Reactant: COc1cccc2c1CC(NC1CC1)CO2
Agent: BrB(Br)Br
Agent: Cl
Agent: N
Solvent: ClCCl
Product: Oc1cccc2c1CC(NC1CC1)CO2
Temperature: -20 °C
Yield: 86.4 %

Procedure:
3-(N-Cyclopropylamino)-5-metoxychroman hydrochloride (5.6 g, 22 mmol) was suspended in CH2Cl2 (140 mL) under N2. The mixture was cooled on a dry-ice/EtOH bath to -20° C. BBr3 (4.1 mL, 44 mmol) dissolved in CH2Cl2 (60 mL) was added to the stirred mixture during 0.5 hour. the yellow clear solution was slowly warmed to 0° C. and kept at that temperature until GC indicated a complete reaction (after 3-5 hours). Then the solution was poured on crushed ice (200 g) and enough conc. NH3 (aq.) to make a pH of 8-9. The mixture was extracted with ether (3×200 mL). The collected ether phases were dried (MgSO4), filtered and concentrated in vacuo to afford a white solid. Crystallization from absolute EtOH afforded 3-(N-cyclopropylamino)-5-hydroxychroman (3.9 g, 88% yield) as colourless needles. Mp 147°-148° C.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CNCCCN
Product: CNCCCNC(=O)Nc1snc(OCc2c(F)cc(C)c(F)c2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-methyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 432 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3C(C)=NN=C3C(C)(C)N=2)=[CH:4][CH:3]=1.Cl.[NH2:27][C:28]1([C:32]([O:34]CC)=O)[CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[NH:12][C:32](=[O:34])[C:28]3([CH2:29][CH2:30][CH2:31]3)[N:27]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)c1nnc(C)n1-2
Reactant: CCOC(=O)C1(N)CCC1
Agent: Cl
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CCC1)C(=O)N2

Procedure:
A procedure analogous to that set forth in the synthesis of Compound 214 was followed, with the exception that ethyl 1-aminocyclobutanecarboxylate hydrochloride was used as starting material. LRMS (M+H)+: 345 m/z.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C12CCCC2
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 105 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 6′-bromospiro[cyclopentane-1,3′-indolin]-2′-one (preparation 2, 0.650 g, 2.44 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (WO200700565, 0.96 g, 3.66 mmol), 1,4-dioxane (25 mL) and a 2M aqueous cesium carbonate solution (3.7 mL, 7.4 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.12 g, 0.15 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 100-110° C. After 20 hours, the mixture was cooled and partitioned between water and ethyl acetate. The combined organic extract was dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (95:5 dichloromethane/methanol) gave the title compound (0.64 g, 81%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].P([O-])([O-])([O-])=O.Br[CH2:26][C:27]([OH:29])=[O:28].Cl>C(O)C>[C:27]([CH2:26][O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])([OH:29])=[O:28]
Reactant: O=C(O)CBr
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OCC(=O)O
Temperature: 25 °C
Reaction time: 240 h
Yield: 74.6 %

Procedure:
To a solution of 0.3 g (1.1 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 30 ml ethanol was added 30 ml 0.5M phosphate buffer pH 7.4. The mixture was added 0.9 g (6.5 mmol) bromoacetic acid and then stirred at 25° C. for 10 days. 4N hydrochloric acid was added to pH 1, and then the reaction mixture was evaporated in vacuo. The residue was stirred with water to give 0.27 g (74%) of 1-carboxymethyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 257° C. 1H-NMR (DMSO-d6): 8.2 (1H, s), 7.6 (1H, s), 4.8 (2H, s).
Reaction SMILES: S(C)C.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][C:13](=O)[NH:12][C:11]=2[CH:17]=1)([O-:6])=[O:5]>C1COCC1>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH2:14][CH2:13][NH:12][C:11]=2[CH:17]=1)([O-:6])=[O:5]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Solvent: C1CCOC1
Solvent: CSC
Product: O=[N+]([O-])c1ccc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A solution of BH3.Me2S in THF (2 M, 7.75 mL, 15.5 mmol) was added dropwise to a suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (0.6 g, 3.1 mmol) in THF (10 mL). The mixture was stirred at room temperature overnight. The reaction was quenched with MeOH (5 mL) at 0° C. and then water (20 mL) was added. The mixture was extracted with Et2O and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a red solid (0.5 g, 89%), which was used without further purification.
Reaction SMILES: [N:1]([C:4]1[C:14]([Cl:15])=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:16][CH3:17])[CH:5]=1)=[N+:2]=[N-:3].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23]CC)=[O:22].[O-]CC.[Na+]>C(O)C>[Cl:15][C:14]1[CH:13]=[C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])[C:6]([O:16][CH3:17])=[CH:5][C:4]=1[N:1]1[C:19]([CH3:26])=[C:20]([C:21]([OH:23])=[O:22])[N:3]=[N:2]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCNC(=O)c1cc(Cl)c(N=[N+]=[N-])cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1cc(Cl)c(-n2nnc(C(=O)O)c2C)cc1OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 28 %

Procedure:
To a solution of 4-azido-5-chloro-N-ethyl-2-methoxybenzamide (1.0 g) obtained in Example 73b) and ethyl 3-keto-n-butanoate (0.61 ml) in ethanol (20 ml) was added 20% sodium ethoxide in ethanol solution (1.85 ml) at room temperature, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-brown solid (0.38 g, 28%). The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:25][CH:21]3[CH2:22][NH:23][CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:6][CH:7]=1.CCN(CC)CC.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:25][CH:21]3[CH2:22][N:23]([C:33](=[O:35])[CH3:34])[CH2:24][CH:20]3[CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16]3)[NH:11][N:10]=2)=[N:6][CH:7]=1
Reactant: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CC2CNCC2C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of 5-chloro-N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (153.3 mg, 0.43 mmol) in DCM (10 mL) were added Et3N (82.3 mg, 0.81 mmol) and acetyl acetate (62.5 mg, 0.61 mmol). The reaction mixture was stirred at rt for 15 min, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (79.0 mg, 46.1%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:16])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[C:3]1[C:23]#[C:24][Si](C)(C)C.O.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[C:23]([C:3]1[N:2]([CH3:1])[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:16])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:4]=1)#[CH:24]
Reactant: Cn1c(C#C[Si](C)(C)C)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.4 %

Procedure:
2-{1-Methyl-4-phenyl-2-[(trimethylsilyl)ethynyl]-1H-imidazol-5-yl}[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 45) (48 mg) was dissolved/suspended in MeOH (3 mL)/water (1 mL) and potassium carbonate (50 mg) added, then stirred for 90 minutes at ambient temperature. The reaction mixture was neutralised with 2M HCl, concentrated in vacuo, the residue diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extracts were dried (MgSO4), filtered, concentrated in vacuo then purified by flash chromatography on silica eluting with 4% MeOH/DCM to give the title compound as a yellow solid (10 mg, 25%);
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=3)=[N:9][C:8]=2[N:7]([CH2:22][CH2:23]C)[C:5]1=[O:6])[CH2:2]C.[NH2:25][NH2:26]>C(O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[CH:16]=[N:17][C:18]([NH:25][NH2:26])=[CH:19][CH:20]=3)=[N:9][C:8]=2[N:7]([CH2:22][CH3:23])[C:5]1=[O:6])[CH3:2]
Reactant: NN
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)nc2n(CCC)c1=O
Solvent: CCO
Product: CCn1c(=O)c2[nH]c(-c3ccc(NN)nc3)nc2n(CC)c1=O
Temperature: 130 °C
Reaction time: 13 h

Procedure:
Compound 1 (500 mg, 1.44 mmol) and hydrazine (4 ml) were put in a pressure tube. Ethanol (30 ml) was added. The pressure tube was flushed with argon, sealed and stirred at 100-160° C. for 10-16 h. After cooling, the resulting solid was collected and washed with methanol and ether to give compound 138 (40 mg). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.[C:28]1(=O)[CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH:28]1([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=4[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCC1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (50 mg, 0.125 mmol, 1.0 equiv; Example 122) in cyclobutanone (469 mg, 0.5 mL, 6.69 mmol, 53.5 equiv; [CAS RN 1191-95-3]) was added acetic acid (28 mg, 27 μL, 0.5 mmol, 4.0 equiv; [CAS RN 64-19-7]) and the reaction mixture stirred at rt. After 90 min, sodium cyanoborohydride (15.7 mg, 0.25 mmol, 2.0 equiv; [CAS RN 25895-60-7]) was added and stirring at rt continued for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 12.5 mg (22%) of the title compound. MS (ISP): 454.2 [M+H]+.
Reaction SMILES: BrBr.[S-:3][C:4]#[N:5].[NH4+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17].O>C(O)(=O)C>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([S:3][C:4]#[N:5])[C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17]
Reactant: COc1ccc(OC)c(O)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(SC#N)c(OC)cc1O
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Bromine (8 g, 2.5 ml) in glacial acetic acid (10 ml) was added dropwise with vigorous stirring over 15 minutes to a mixture of ammonium thiocyanate (8 g), 2,5-dimethoxyphenol (7.7 g), and glacial acetic acid (50 ml) kept at 15°-20°. The mixture was left at room temperature for 30 minutes and then poured into water (400 ml). A solid separated which was filtered off, washed with water and dried in vacuo to give the thiocyanatophenol (7 g). RfE 0.36.
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:26]([CH3:27])=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20](I)[CH:19]=1>>[F:17][C:18]1[C:26]([CH3:27])=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:19]=1
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Reactant: Cc1cc(C(=O)O)c(I)cc1F
Product: Cc1cc(C(=O)O)c(-n2nccn2)cc1F

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 4-fluoro-2-iodo-5-methylbenzoic acid. MS (ESI) 222 (M+H).