Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>O>[CH:2]([S:4][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])([CH3:3])[CH3:1]
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(SC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of propane-2-thiol (3.30 mL), potassium carbonate (6.60 g) and DMF (40 mL), 1-fluoro-4-methyl-2-nitrobenzene (4.85 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction liquid was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1-(isopropylsulfanyl)-4-methyl-2-nitrobenzene (6.60 g) as a yellow oil.
Reaction SMILES: C([S:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=[N:14][O:15][CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[O:10]1)(=O)C.[OH-].[K+]>CO>[CH3:16][O:15][N:14]=[C:13]([C:9]1[S:4][CH2:5][CH2:6][O:7][N:8]=1)[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[OH:10]
Reactant: CON=C1C(=NOCCSC(C)=O)Oc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C1=NOCCS1)c1ccccc1O
Yield: 24.7 %

Procedure:
Process c) 3.67 g (0.0125 mol) of S-[2-(3-methoxyimino-3H-benzofuran-2-ylideneaminooxy)-ethyl] thioacetate in 40 ml of methanol are heated under reflux with 12.5 ml of 2N aqueous potassium hydroxide solution for 15 minutes. The solvent is then distilled off under reduced pressure and the residue is admixed with 2N aqueous hydrochloric acid. The mixture is extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is stirred with diethyl ether, giving 0.78 g (24.7% of theory) of (5,6-dihydro-[1,4,2]oxathiazin-3-yl)-(2-hydroxyphenyl)-methanone O-methyloxime.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:5]1[CH2:4][CH:3]1[CH2:1][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[O:15]
Reactant: NC(=O)Nc1ccccc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)Nc1ccccc1OCC1CO1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A solution of epibromohydrin (0.94 g, 6.84 mmol) in dry DMF (2 mL) was added dropwise to a stirred suspension of N-(2-hydroxyphenyl)urea (0.65 g, 4.27 mmol) and cesium carbonate (2.22 g, 6.84 mmol) in DMF (8 mL). After 2 hours the mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with water (3 times), dried and concentrated. The semi-solid residue was disssolved in dichloromethane/ethyl ether, filtered and heptane was added to turbidity. After standing at room temperature overnight, the solid was filtered to afford the subtitle compound (0.28 g, 32%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([O:16][CH3:17])=[CH:9][C:4]=1[C:5](OC)=[O:6].C[CH2:19][N:20](CC)CC.CN.CCO.Cl>CO.CCOC(C)=O>[CH3:17][O:16][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][N:20]([CH3:19])[C:5]2=[O:6])=[CH:12][C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1CBr
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C)C2=O
Temperature: 70 °C
Yield: 75.2 %

Procedure:
To methyl 2-(bromomethyl)-5-methoxy-4-nitrobenzoate (212 mg, 0.7 mmol) in methanol (6 mL) was added Et3N (0.12 mL, 0.84 mmol) and methylamine in EtOH (0.11 mL, ˜8 M in EtOH, 0.84 mmol). The mixture was heated to 70° C. for 5 h. and then EtOAc (30 mL) and 2M HCl(aq) (30 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane then EtOAc-10% MeOH in DCM) gave 6-methoxy-2-methyl-5-nitroisoindolin-1-one (117 mg, 75%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=223 at 3.02 min. 1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.53 (s, 1H), 4.40 (s, 2H), 4.02 (s, 3H), 3.24 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH:11]1([O:16][C:17]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COc1ccc(-c2ccc(Cl)cc2)cc1OC1CCCC1
Yield: 92 %

Procedure:
Following the procedure of Example 1, 4-chloro-phenylboronic acid and 3-cyclopentyloxy-4-methoxybromobenzene yielded 92% of the title compound as white needles: mp 94°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:5]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH2:33](I)[CH3:34]>O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH2:33][CH3:34])[CH:5]=1
Reactant: COC(=O)c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cnc2c(Nc3cccc(C(=O)OC)c3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A 750 ml flask is charged with 25.4 g (83.5 mmol) of 3-(2-chloro-9H-purin-6-yl-amino)-benzoic acid methyl ester, 12.95 g (93.7 mmol) of K2CO3 and 360 ml of DMF. The mixture is stirred at RT for 30 min, then 35.8 ml (443 mmol) ethyliodide are added under slight cooling. After completion, the mixture is poured into water/EtOAc (1.2 l each). The aqueous layer is extracted with ethyl acetate (2 fold). The combined organic layers are washed with water and brine, dried (Na2SO4), filtered and concentrated. After purification by chromatography (silica gel, EtOAc) the desired product, 3-(2-chloro-9-ethyl-9H-purin-6-yl-amino)benzoic acid methyl ester, (19.1 g, 69% yield) is obtained; Rf=0.25; (EtOAc); m.p. 148° C.; ESI-MS: 332 (M+H)+.
Reaction SMILES: C(C(C([O:10][C:11]([C:14]([O:17][C:18]([C:21]([O:24][C:25]([C:31]([O:34]C(C(C(F)(F)F)(F)F)=O)(F)[F:32])([C:27]([F:30])([F:29])[F:28])[F:26])([F:23])[F:22])([F:20])[F:19])([F:16])[F:15])(F)[F:12])=O)(F)F)(F)(F)F.[F-].[K+]>>[F:12][C:11]([C:14]([O:17][C:18]([C:21]([O:24][C:25]([C:31]([F:32])=[O:34])([C:27]([F:28])([F:29])[F:30])[F:26])([F:22])[F:23])([F:20])[F:19])([F:16])[F:15])=[O:10]
Reactant: O=C(OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Product: O=C(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(C(=O)F)C(F)(F)F
Temperature: 40 °C

Procedure:
CF3CF2COO(CF2)2O(CF2)2OCF(CF3)CF2OCOCF2CF3 (5.1 g) obtained in Example 5-4 was charged together with 0.09 g of KF powder into a flask and heated at 40° C. for 2 hours in an oil bath while vigorously stirring. At an upper portion of the flask, a reflux condenser adjusted to a temperature of 20° C. and a gas-collecting fluororesin container were installed in series. After cooling, a liquid sample (3.2 g) and a gaseous sample (1.6 g) were recovered. By GC-MS, it was confirmed that the gaseous sample contained CF3CF2COF as the main product, and the liquid sample contained the above-identified compound as the main product. Further, the 19F-NMR yield of the above-identified compound contained in the product was 92%.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[I:12].[CH2:13](O)[CH2:14][OH:15].Cl[Si](C)(C)C>ClCCl>[O:7]1[CH2:13][CH2:14][O:15][CH:6]1[C:5]1[CH:8]=[C:9]([O:10][CH3:11])[C:2]([OH:1])=[C:3]([I:12])[CH:4]=1
Reactant: OCCO
Reactant: COc1cc(C=O)cc(I)c1O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: COc1cc(C2OCCO2)cc(I)c1O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (20 g, 72 mmoles), ethylene glycol (8.0 mL, 144 mmoles), and chlorotrimethylsilane 36.5 mL, 0.29 moles) in dichloromethane (300 mL) was heated at reflux for 16 hours. The mixture was cooled to room temperature and washed with saturated sodium hydrogencarbonate (3×200 mL). The combined aqueous phases were; extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 22.1 g (95%) of 4-[1,3]dioxolan-2-yl-2-iodo-6-methoxy-phenol. M.p. 120-121° C.
Reaction SMILES: [F-:1].[K+].C(O)COCCO.C1(C)C=CC=CC=1.Br[CH:18]([C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:23])[CH2:19][CH2:20]Cl>O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:18]2([F:1])[CH2:20][CH2:19]2)=[O:23])=[CH:25][CH:26]=1
Reactant: [F-]
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)C1(F)CC1
Temperature: 100 °C
Yield: 10.1 %

Procedure:
2000 g (34.5 mol) of potassium fluoride are introduced into 7 liters of diethylene glycol, and the mixture is treated with 500 ml of toluene at room temperature. The toluene is distilled off at 150° C., and the mixture is then allowed to cool to 100° C., and 1500 g (5 mol) of 4-chloro-phenyl 1-bromo-3-chloro-n-propyl ketone are added in portions in the course of 15 minutes. The reaction mixture is heated for 4 hours at 150° C. and then cooled and poured into 10 liters of water. The resulting mixture is extracted five times with 2 liters of toluene per extraction, and the combined organic phases are washed with water, dried over magnesium sulphate and concentrated by stripping off the solvent under reduced pressure. The residue which remains is distilled under a high vacuum, and the distillate collected is subjected to fractional distillation under a high vacuum, using a spinning band column. In this manner, 100 g (10% of theory) of 1-fluoro-cyclopropyl 4-chlorophenyl ketone are obtained in the form of a liquid of boiling point 70°-76° C. at 0.03 mbar.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:15]=[C:14]([C:16]2[C:25]3[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[S:28][C:24]=3[C:23]([Br:33])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)[CH:13]=[C:12]([Br:34])[C:5]=1[O:6][CH2:7][C:8]([O:10]C)=[O:9]>C1COCC1.CO.O>[Br:3][C:4]1[CH:15]=[C:14]([C:16]2[C:25]3[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[S:28][C:24]=3[C:23]([Br:33])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)[CH:13]=[C:12]([Br:34])[C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 2.5 h
Yield: 91 %

Procedure:
1.0 N Aqueous potassium hydroxide (2.66 mL, 2.66 mmol) was added to a stirred suspension of [2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl )-phenoxy]-acetic acid, methyl ester (1.51 g, 2.37 mmol) in THF (13 mL) and methanol (4 mL). Dissolution occurred. After 2.5 h at ambient temperature, the reaction mixture was diluted with water and extracted with ether (100 mL). The aqueous phase was acidified with 10% aqueous HCl and filtered. The solid was washed with water and triturated with pet. ether. The solid was dried in vacuo at 70° C. to provide the title compound as a white solid (1.34 g, 91%): mp 259-261° C.: NMR (DMSO-d6): δ8.29 (dd, J=8, 1 Hz, 1 H), 8.06 (dd, J=8, 1 Hz, 1 H), 7.82 (s, 2 H), 7.79 (ddd, J=8, 6, 2 Hz, 1 H), 7.61 (m, 2 H), 7.52 (ddd, J=8, 7, 1 Hz, 1 H), 7.32 (ddd, J=8, 7, 1 Hz, 1 H), 6.73 (dd, J=8, 1 Hz, 1 H), 4.78 (s, 2 H); MS (EI): [M+], 3 bronine isotope pattern, 618 (30%), 620 (90%) 622 (100%) 624 (50%); Anal. Calc. for C24H13Br3O3S: C, 46.41, H, 2.11, N, 0.00. Found: C, 46.38, H, 1.99, N, 0.01.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl[CH2:14][C:15]([OH:17])=[O:16].Cl>O>[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1ccc(OCC(=O)O)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Into a 100 ml. flask there were placed 100 gms. sodium hydroxide in 300 ml. water and the mixture was stirred until all of the sodium hydroxide was dissolved. Without cooling, there were added 60 gms. p-isopropylphenol and 95 gms. chloroacetic acid. The mixture was stirred at a temperature between 95 and 105° C. for 1 hour and then cooled to 40° C. The reaction mixture was adjusted to a pH of approximately 2 by addition of 1 molar HCl, the mixture was cooled to room temperature and extracted with 2×300 ml. ether. Upon treatment of the ether layer with sodium carbonate solution, the sodium salt of the product precipitated. The salt was dissolved in 800 ml. water and acidified with hydrochloric acid to precipitate product. It was filtered, washed with water and dried to afford 25.6 gms. product, m.p. 84.5°-87° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:15]=[C:7]2[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][N:6]2[N:5]=1
Reactant: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A 50-mL single-neck round-bottomed flask was purged with nitrogen and charged with 124e (492 mg, 2.34 mmol), 10% palladium on carbon (50% wet, 234 mg), and methanol (20 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 2 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 124f (380 mg, 80%). MS: [M+H]+ 181.1
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[NH:7][C:8]([O:10][C:4]2=[CH:3][CH:2]=1)=[O:9].[CH3:11][NH:12][CH2:13][CH2:14][OH:15].CO>C(OCC)C>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([N:12]([CH3:11])[CH2:13][CH2:14][OH:15])=[O:9]
Reactant: CNCCO
Reactant: O=c1[nH]c2ccccc2o1
Solvent: CCOCC
Solvent: CO
Product: CN(CCO)C(=O)Nc1ccccc1O
Temperature: 75 °C

Procedure:
Benzoxalinone (202 g) and N-methylethanolamine (133 g) were stirred and heated at 75° C. for 3 hours, then cooled to 65° C. and methanol (50 ml) was added. The mixture was cooled to ambient temperature and diethyl ether (750 ml) was added. The precipitate was filtered off and recrystallised from methanol to give the desired urea which had a m.pt. of 128° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(=O)[nH]c1C
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(=O)[nH]c1C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
5,6-Dimethyl-2-pyridone (1-013-03) (3.695 g) was dissolved in conc. sulfuric acid (38 mL) under ice-cooling, and the reaction mixture was stirred under ice-cooling, and then to the reaction mixture was added dropwise 70% nitric acid (3.53 mL) at 3 to 5° C. as internal temperature for 50 min, and then the reaction mixture was stirred. After 2 h, the reaction mixture was poured gradually into ice and the resulting crystal was filtered. The crystal was washed with water to give 5,6-dimethyl-3-nitro-2-pyridone (1-013-04) (3.102 g, 61.5%, m.p.:251-257 (dec)). Furthermore the aqueous layer was extracted five times with chloroform, the organic layer was dried over magnesium sulfate, and evaporated under reduced pressure. The resulting crystal was filtered to give an additional 5,6-dimethyl-3-nitro-2-pyridone (1-013-04)(271 mg, 5.4%).
Reaction SMILES: [N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17](Cl)[N:16]=[N:15][C:14]=3[C:20]([NH2:22])=[O:21])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[N:1]1[N:2]([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]4[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:16]=[N:15][C:14]=3[C:20](=[O:21])[NH2:22])[CH:9]=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2nccn2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3nccn3)n2)c(C(N)=O)nn1
Temperature: 140 °C
Yield: 56.3 %

Procedure:
To a solution of 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (90 mg, 284 μmol) in NMP (947 μL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (122 mg, 568 μmol) and the mixture heated to 140° C. for 16 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (61 mg, 284 μmol) was added and the mixture heated for a further 16 h. The reaction mixture was cooled, diluted with ethyl acetate and brine, then the phases were separated and the organic phase collected and washed with brine (2×). The organic layer was concentrated in vacuo then purified by chromatography (silica, 2-5% methanol in dichloromethane) to give a residue that was triturated with ethyl acetate, filtered, and washed with ether to give tert-butyl (1S,2R)-2-(5-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (79 mg, 160 μmol, 56%) as a brown solid. MS (EI/CI) m/z: 495.1 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]=[C:6]3[C:11]4[C:16]([CH2:17][C:5]3([CH3:18])[C:4]=2[CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[CH3:19][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH3:19][C@@:6]12[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][C@:5]1([CH3:18])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=1[NH:7]2
Reactant: Cc1ccc2c(c1)C1(C)Cc3ccccc3C1=N2
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc2c(c1)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 9b,10-dihydro-8,9b-dimethylindeno[1,2-b]indole, (5.05 g, 0.022 mol) in dry tetrahydrofuran (100 cm3) at -78° C., under nitrogen, in a flame dried flask, was added dropwise methyllithium, (1.4M solution in diethyl ether, 23.2 cm3, 0.032 mol). The mixture was stirred at -78° C. for 2 hours and then at -15° C. for a further 1 hour. Saturated ammonium chloride solution (3 cm ) was then added and the mixture allowed to warm to room temperature. The reaction mixture was portioned between ether and saturated ammonium chloride solution and the layers separated. The aqueous phase was extracted with diethyl ether (2×25 cm3) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to afford the title compound as an off white solid. This was purified by flash chromatography on silica gel eluting with 3-10% ethyl acetate/60°-80° petrol to yield a colourless solid. Yield: 2.73 g, 51% .M.p. 208°-212° C. 1H NMR (CDCl3) δ: 7.1-7.3 (4H, m), 6.94 (1H, m), 6.77 (1H, d, J=7.8 Hz), 6.46 (1H, d, J=7.8 Hz), 3.35 (1H, d, J=15.9 Hz), 3.06 (1H, d, J=15.9 Hz), 2.22 (3H, s), 1.46 (3H, s), 1.34 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13]C)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: COc1ccc(Cl)c2c1CCC(=O)N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1CCc2c(O)ccc(Cl)c2N1
Temperature: 0 °C
Yield: 65.9 %

Procedure:
The thus-obtained 13 g of 8-chloro-5-methoxy-3,4-dihydrocarbostyril and 35 g of aluminum chloride are dispersed in 30 ml of benzene and heated for 2 hours under refluxing conditions. The reaction mixture is poured into ice-water and the precipitate thus formed is separated by filtration, washed with water and dried. Recrystallization from isopropanol obtains 8 g of 8-chloro-5-hydroxy-3,4-dihydrocarbostyril in the form of colorless need-like crystals with a melting point of 206°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.C(P(CCCC)CCCC)CCC.CN(C(/N=N/C(N(C)C)=O)=O)C>>[CH3:28][O:29][C:30](=[O:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:35][CH:34]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)COc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Product: COC(=O)COc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), (4-hydroxy-phenoxy)-acetic acid methyl ester (commercially available), tri-n-butylphosphin and N,N′,N′-tetramethylazodicarboxamide. The compound was purified by preparative HPLC (phenomenex gemini column) eluting with a gradient of acetonitril:water (50:50 to 95:5). Colorless oil. MS (Turbo Spray): m/z=555.2 [M+H].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1.[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>CCO>[CH2:12]([O:14][C:15]1[C:18](=[O:19])[C:17](=[O:22])[C:16]=1[NH:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1)[CH3:13]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cncc(C(F)(F)F)c1
Solvent: CCO
Product: CCOc1c(Nc2cncc(C(F)(F)F)c2)c(=O)c1=O
Yield: 38 %

Procedure:
A solution of the product from Example 52A (2.98 g, 18.4 mmol) and 3,4,-diethoxy-3-cyclobutene-1,2-dione (3.13 g, 18.4 mmol) in EtOH (50 mL) was heated at reflux for 48 hours. The reaction mixture was filtered while still hot and the filtrate was absorbed onto silica gel. The crude material was purified by chromatography, eluting with EtOAc/hexanes (3:1) to provide 2.00 g (38% yield) of the desired compound as colorless crystals.