Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N+](C1C=CC(S(O[CH2:34][C:35]([C@@H:38]2[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]2)([CH3:37])[CH3:36])(=O)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:37][C:35]([C@@H:38]4[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]4)([CH3:34])[CH3:36])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: CC1(C)OC[C@@H](C(C)(C)COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](C(C)(C)COc2cccc3ccc(-c4nnc5ccccn45)nc23)O1
Temperature: 85 °C
Yield: 7.5 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (0.25 g, 0.95 mmol), (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl 4-nitrobenzenesulfonate (0.41 g, 1.1 mmol) and cesium carbonate (0.62 g, 1.9 mmol) were added to minimal amount of N,N-dimethylacetamide and heated to 85° C. The reaction was cooled, ethyl acetate was added and the mixture was sonicated. Solids were filtered off and the filtrate was dried over MgSO4, filtered and evaporated. The crude material was purified on silica gel using isopropyl alcohol containing 2% NH4OH and DCM to yield 30 mg of the desired product (90% pure. The crude material was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=O)[CH2:3]1.B.CSC>O1CCCC1>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COc1cc2c(cc1[N+](=O)[O-])NCCC2(C)C
Yield: 56.3 %

Procedure:
A solution of 4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (2.5 g, 10 mmol) in tetrahydrofuran (45 mL) was treated with borane-dimethylsulfide complex (20.5 mL, 41 mmol, 2 M in THF, Acros Organics). The mixture was heated at reflux for 16 h, cooled, quenched carefully via dropwise of excess methanol, concentrated, and purified by column chromatography on SiO2 (0 to 100% ethyl acetate/dichloromethane) to obtain 4,4-dimethyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (1.33 g, 5.63 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6 H), 1.58-1.65 (m, 2 H), 3.13-3.21 (m, 2 H), 3.79 (s, 3 H), 5.95 (bs, 1 H), 6.96 (s, 1 H), 7.06 (s, 1 H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:28][CH:29]=[C:30]([Cl:32])[CH:31]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[C:26]([Cl:25])=[CH:31][C:30]([Cl:32])=[CH:29][N:28]=4)[CH2:34][CH2:35]3)=[O:16])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1)N1CCN(c2ncc(Cl)cc2Cl)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(3,5-dichloro-2-pyridinyl)piperazine to give the title compound as a colorless solid. MS: 566.3 ([M+H]+)
Reaction SMILES: [OH:1][CH:2]([CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:3][O:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[H-].[Na+].S(OC)(O[CH3:39])(=O)=O.Cl>CN(C=O)C>[CH3:39][O:1][CH:2]([CH2:21][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:3][O:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CCCN(CC(O)COC(Cc1ccccc1)C(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CC(COC(Cc1ccccc1)C(=O)c1ccccc1)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
5 g. (11.3 mMol) 2-[2-hydroxy-3-(tert.-butyloxycarbonyl-propylamino)-propoxy]-3-phenyl-propiophenone are dissolved in 50 ml. abs. DMF and mixed at 0° C. with 0.30 g. (12.5 mMol) sodium hydride. Thereafter, it is stirred for 70 minutes at room temperature. Subsequently, the reaction mixture is cooled to 0° C. and a solution of 1.60 g. (12.5 mMol) dimethyl sulphate in 5 ml. absolute DMF added dropwise thereto. After 40 minutes at 0° to 5° C., the reaction mixture is emptied into 2N HCl. The phases are separated and the H2O phase extracted three times with CH2Cl2. The combined organic phases are after drying over Na2SO4, evaporated. There are obtained 4.5 g. of an orange oil which is purified column chromatographically. Column chromatography: silica gel, Bz:EE=14:1. The purified oil crystallises in a low-cooling cabinet.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[NH2:7])[CH3:2].CCN(C1C=CC=CC=1)CC.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:7][C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCOc1ccc(N)cc1OCC
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: c1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)cc1OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
3,4-Diethoxyaniline (1.8 g) and diethylaniline (1.5 g) were dissolved in benzene (20 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.2 g) in 5 minutes under ice-cooling. After being allowed to stand at room temperatue for 3 hours, the reaction mixture was poured into ice-water and extracted with ether. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give crude crystals (2.6 g). Recrystallization from ethanol gave isopropyl N-(3,4-diethoxyphenyl)carbamate (Compound No. 13) (2.3 g) in a yield of 86%. M.P., 100°-100.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=O)[CH:15]=[N:14]1.[CH3:20][S:21][CH2:22][S:23]([CH3:25])=[O:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[C:22]([S:21][CH3:20])[S:23]([CH3:25])=[O:24])[CH:15]=[N:14]1
Reactant: CSCS(C)=O
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: C1CCOC1
Solvent: CO
Product: CSC(=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)S(C)=O

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde [15 g) and methyl methylthiomethyl sulphoxide (6 ml) were heated under reflux in tetrahydrofuran (100 ml) containing Triton B solution (6 ml; 40% in methanol) for 12 hours. The mixture was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-methylthio-2-methylsulphinylvinyl)- 2H-1,2,3-triazole, m.p. 122°-123°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].C(OCC)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:28][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=1)[CH3:12]
Reactant: Br[Mg]Cc1ccc2ccccc2c1
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (900 μL, 5.06 mmol) in THF (15 mL) was added slowly a diethyl ether solution of (2-naphtalenylmethyl)magnesium bromide (21) (0.25 M, 25.0 mL, 6.25 mmol) at −78° C. After stirring at for 2.5 h at −78° C., the mixture was gradually warmed to room temperature and stirred for 15 h. To this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate═19/1) to give 1,1-diethoxy-3-(2-naphthalenyl)propan-2-one (22) as a colorless oily substance (675 mg, 2.48 mmol, 49.0%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C[Mg+].[Br-].[CH2:15](OCCCC)CCC>C1COCC1>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]([OH:5])[CH3:15]
Reactant: CCCCOCCCC
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General Procedure CC: To a solution of 2,3,6-trichlorobenzaldehyde (1.00 g, 4.77 mmol) in THF (10 mL) was added MeMgBr/butyl ether (1M, 5.72 mL, 5.72 mmol) at 0° C. under nitrogen, the resulting mixture was allowed to warm to rt and stirred overnight. The mixture was quenched with sat. aq. NH4Cl (15 mL) at 0° C., then diluted with Et2O (15 mL), the organic phase was washed with brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.69 (d, J=6.8 Hz, 3H), 2.97 (br. s., 1H), 5.67 (q, J=6.8 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 7.35-7.38 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=O)[N:11]=[C:4]2[N:3]=1.[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([CH2:37][CH3:38])[CH:30]=3)[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([CH2:37][CH3:38])[CH:30]=3)[O:24][C:23](=[O:25])[C:22]([CH2:12][C:10]3[N:11]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]4[N:9]=3)=[C:21]([OH:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(F)c1O
Solvent: CO
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc(F)c1O
Reaction time: 0.25 h

Procedure:
5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.2 g, 0.57 mmol) was added to a solution of 6-Cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (0.2 g, 0.53 mmol) in MeOH (6 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (50 mg, 0.86 mmoL). After 15 hours the reaction mixture was quenched with 1N HCl and extracted with 10% MeOH in CH2Cl2. The combined organic layers were concentrated and recrystallized from EtOAc to give the product as a white soild (0.15 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 1.09 (t, J=7.3 Hz, 3 H), 1.43–1.72 (br m, 8 H), 2.05–2.17 (m, 2 H), 2.43 (m, 1 H), 2.48–2.58 (m, 10 H), 2.66 (d, J=17.4 Hz, 1 H), 2.81 (d, J=17.4 Hz, 1 H), 3.74 (d, J=16.2 Hz, 1 H), 3.85 (d, J=16.2 Hz, 1 H), 6.76 (s, 1 H), 6.84 (d, J=11.6 Hz, 1 H) 7.07 (s, 1 H), 9.08 (s, 1 H), 11.01 (s, 1 H). MS: C28H32N4O4F (M+H+) 509.10.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CCN(C(C)C)C(C)C>CC(O)C>[C:11]12([NH:10][C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]3)[CH2:12]1)[CH2:20]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(NC23CC4CC(CC(C4)C2)C3)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of 4,6-dichloropyrimidine, 252 mg of 1-aminoadamantane hydrochloride and 452 mg of DIPEA were dissolved in 2 mL of i-PrOH and the mixture obtained was charged into a screw cap vial and the vial was kept overnight in a heating block at 90° C. The reaction was monitored by TLC and was completed after 12 hours. The mixture obtained was cooled to r.t., solvent was evaporated and N-adamant-1-yl-6-chloropyrimidin-4-amine was obtained by column chromatography using PE:EtOAc 10:1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22]([CH2:33][CH3:34])[C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH:27](Br)[C:26]1=O)=[O:24])[CH3:21]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:33]([N:22]([CH2:20][CH3:21])[C:23]([CH:25]1[C:26]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=3)[N:12]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:27]=2[CH2:28][CH2:29][CH2:30]1)=[O:24])[CH3:34]
Reactant: O=C(COCc1ccccc1)Nc1ccc(F)cc1
Reactant: CCN(CC)C(=O)C1CCCC(Br)C1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
A mixture of 2-benzyloxy-N-(4-fluoro-phenyl)-acetamide (33) (5.3 g, 22 mmol) and 3-bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35) (3.0 g, 13 mmol)) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (30 mL) and dry zinc chloride (9.0 g, 66 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with 2 N HCl (100 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10-50% B, 100 g) to afford 196 mg (11%) of 9-(2-benzyloxy-ethyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (36) as a white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.14 (3H, t, J=7 Hz, N(CH2CH3)2), 1.30 (3H, t, J=7 Hz, N(CH2CH3)2), 1.60-2.60 (4H, m, 2- and 3-CH2), 2.70-2.85 (2H, m, 1-CH2), 3.10-3.65 (4H, m, N(CH2CH3)2 and NCH2CH2OBn), 3.66-3.75 (1H, m, 4-CH), 4.00-4.25 (2H, m, NCH2CH2OBn), 4.41 (2H, s, OCH2Ph), 6.75-6.95 (2H, m, NCCHCHCFCH), 7.05-7.15 (1H, m, NCCHCHCFCH), and 7.16-7.25 (5H, m, Ph).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>O>[CH2:23]([C:22]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:25])[CH3:24]
Reactant: CCC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (188 mg, 1 mmol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and propionyl chloride (101 mg, 1.10 mmol) followed by stirring at 60° C. for 3 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (30/1) as an elution solvent. The yield was 66.4 mg (27%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[O:38][C:39]2[C:45]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[O:38][C:39]3[C:45]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:44][CH:43]=[CH:42][C:40]=3[CH:41]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1cccc2cc(CCl)oc12
Product: COCCCOc1cccc2cc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)oc12

Procedure:
Analogously to Method D, 0.339 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy) propoxy]phenyl}piperidine-1-carboxylate and 0.215 g of 2-chloromethyl-7-(3-methoxypropoxy)benzofuran are reacted. The title compound is obtained as a yellow oil. Rf=0.37 (1:2 EtOAc-heptane); Rt=6.26.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[N:6][CH:7]=1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:10]3[N:19]=[C:18]([NH:20][C:21]4[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=4)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[O:29][CH2:28][CH2:27][O:9]2)=[N:6][CH:7]=1
Reactant: OCCO
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2nc(C3(c4ccc(F)cn4)OCCO3)nc3ccccc23)n[nH]1
Temperature: 25 °C

Procedure:
To a mixture of (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 1 and toluene are added ethylene glycol 5 equiv) and p-toluenesulfonic acid monohydrate (0.2 equiv), and the mixture is heated at reflux while collecting water in a Dean-Stark trap. As needed, additional ethylene glycol and p-toluenesulfonic acid monohydrate are added and heating and water collection are continued to achieve substantially complete reaction After cooling to rt, the mixture is concentrated, and the residue is dissolved in DMSO and purified by reverse phase HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(Nc1cc(-c2cnccn2)ccc1[N+](=O)[O-])N1CCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cnccn2)cc1NC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 1 N-(2-nitro-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.11 g, 0.35 mmol) in methanol (6 mL) and THF (6 mL) was added Pd/C (0.04 g, 0.94 mmol, 0.33 equiv.). The reaction mixture was degassed then stirred at room temperature under H2 atmosphere for 1h. The reaction was filtered through celite and concentrated. The crude solid was washed with ether, and dried under reduced pressure to obtain of pure N-(2-amino-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.07 g, 70% yield). ESI+ MS: m/z 284 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.30 (s, 1H), 8.55 (s, 1H), 8.40-8.39 (m, 1H), 7.88 (s, 1H), 7.71-7.69 (m, 1H), 7.53 (s, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.31 (s, 2H), 3.40-3.37 (m, 4H), 1.86 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:24])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:24][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][CH2:21]1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COC1CCN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CCN(CCOc2ccc(NC(=O)c3cccc(F)c3)cc2-c2c(Br)cnn2C)CC1
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(4-methoxypiperidin-1-yl)ethoxy)benzenamine (0.024 g, 0.060 mmol) in CH2Cl2 (0.9 mL) was added 3-fluorobenzoyl chloride (0.0086 mL, 0.0714 mmol) and triethylamine (0.011 mL, 0.077 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.027 g, 56%). LCMS m/z (%)=531 (M+H79Br, 94), 533 (M+H81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.42 (s, 1H), 7.95 (dd, J=2.1, 8.5 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.79-7.75 (m, 1H), 7.74-7.72 (m, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.63-7.57 (m, 1H), 7.45 (dt, J=2.6, 8.3 Hz, 1H), 7.29 (dd, J=3.7, 9.1 Hz, 1H), 4.47-4.38 (m, 1H), 4.35-4.28 (m, 1H), 3.69 (s, 3H), 3.27 (s, 3H), 3.53-1.37 (m, 11H).
Reaction SMILES: [CH2:1](F)[O:2][CH:3]([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)C(F)(F)F.BrC[C:25]([O:27]CC)=[O:26]>>[F:5][C:4]([F:7])([F:6])[CH:3]([O:2][CH2:1][C:25]([OH:27])=[O:26])[C:8]([F:11])([F:10])[F:9]
Reactant: CCOC(=O)CBr
Reactant: FCOC(C(F)(F)F)C(F)(F)F
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: O=C(O)COC(C(F)(F)F)C(F)(F)F
Yield: 66 %

Procedure:
U.S. Pat. No. 6,271,422 describes the synthesis of sevoflurane by fluoromethylation of alcohols via decarboxylative halogenation. In this way, hexafluoroisopropanol is submitted to reaction with ethyl alpha-bromoacetate providing alpha-(hexafluoroisopropoxy) acetic acid in a yield of 66%. This intermediate is subjected to reaction with the highly toxic lead tetra-acetate, using the carcinogenic benzene as the solvent. In the reaction sequence, the homogeneous benzene/sevochlorane solution, which is inseparable by distillation, is reacted with potassium fluoride providing at the end of the process sevoflurane with a low yield of 28%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>ClCCl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]([S:14](=[O:16])(=[O:15])[NH:28][CH:25]1[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCC(N)CC1
Reactant: CC(CNC(=O)OCc1ccccc1)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1CCC(NS(=O)(=O)C(C)CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
245 mg (0.84 mmol) of crude (2-chlorosulfonyl-propyl)-carbamic acid benzyl ester in 3 ml dichloromethane were added dropwise to a solution of 143 mg (1.2 equiv.) 1-isopropyl-piperidin-4-ylamine and 214 μl DIPEA in 3 ml dichloromethane. After 2 h stirring at room temperature the reaction mixture was washed with 5 ml of a saturated NaHCO3-solution. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure to give crude [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-propyl]-carbamic acid benzyl ester as yellow oil.