Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[C:6]([N:8]([CH3:16])[CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:7]=1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:4]1[CH:5]=[C:6]([N:8]([CH3:16])[CH:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:22]
Reactant: CN1CCC(N(C)c2cc(N)cc(F)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Product: CN1CCC(N(C)c2cc(F)cc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Combine 5-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 29, 0.036 g, 0.15 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.044 g, 0.23 mmol) and 1,4-doxane (2 mL), stir and heat at reflux. After 3 hr, cool to ambient temperature. Load on a SCX column (10 g), wash with methanol, elute with 2M ammonia-methanol. Concentrate eluent to obtain 0.059 g (100%) the title compound as a free base. Dissolve this material in dichloromethane (5 mL) and treat with 1M hydrochloric acid in ether (0.15 mL, 0.15 mmol). Concentrate to give the title compound as a brown powder: high resolution mass spectrum: Obs. m/z 394.1495; Calc. m/z 394.1497; 1H NMR (CDCl3)of free base: 7.8 (bs, 1H), 7.7 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 6.8 (s, 1H), 6.7 (m, 1H), 6.2 (m, 1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of (4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (5.80 g, 26.9 mmol) in dry methylene chloride (67 mL) was added in order activated 3 Å molecular sieves (6.54 g), 4-methylmorpholine N-oxide (5.04 g, 43.0 mmol) and tetrapropylammonium perruthenate (380 mg, 1.08 mmol). The mixture was stirred at 25° C. for 18 h under nitrogen then the mixture was concentrated. Purification by column chromatography on silica gel with hexane/ethyl acetate (1:1) afforded (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester as a white solid (5.52 g, 96%). 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.64-1.74 (m, 2H), 2.21-2.27 (m, 2H), 2.39-2.45 (m, 4H), 3.97 (bs, 1H), 4.40 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=[O:12])[CH2:10][CH3:11].Cl>>[C:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Cl
Reactant: Oc1ccccc1Cl
Agent: Cl
Product: CCC(=O)Oc1ccccc1Cl
Temperature: 100 °C
Yield: 85.4 %

Procedure:
o-Chlorophenol (64 g, 0.5 mole) and propionyl chloride (50 g, 0.55 mole) were mixed at room temperature and then heated at 100° C. (steam bath) for 2-3 hrs. Hydrogen chloride gas was evolved. After 2-3 hrs the reaction mixture was distilled in vacuo and gave 78.8 g (86%) of o-chlorophenyl propionate, bp 11 mm=111° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10](F)=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH2:5][CH2:4]1)[CH3:2].C([OH:22])C#CC.[K].CC(C)([O-])C.Cl>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([OH:22])=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(c2cccc(C#N)c2F)CC1
Reactant: CC#CCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: CS(C)=O
Product: CCN1CCC(c2cccc(C#N)c2O)CC1
Temperature: 125 °C

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorobenzonitrile (10 mg, 0.031 mmol) in dimethylsulfoxide (1 ml) was added 2-butyn-1-ol (4.3 mg, 0.062 mmol) and potassium-tertbutoxide (7 mg, 0.063 mmol). The mixture was heated to 125° C. in a sealed tube under microwave radiation for 120 s. Aqueous hydrochloric acid (10%, 10 ml) was added and the aqueous phase was washed with diethyl ether (2×20 ml). The aqueous phase was basified by addition of sodium hydroxide (5 M, 5 ml) and extracted with ethyl acetate (3×20 ml). The combined organic phase was dried (MgSO4) and evaporated under reduced pressure to give the title compound. MS m/z (relative intensity, 70 eV) 230 (M+, 60), 229 (24), 216 (23), 215 (bp) 110 (30).
Reaction SMILES: [C:1]1([C:7]2(C(O)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:13]=[N+]=[N-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.C(Cl)Cl>[C:1]1([C:7]2([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NC1(c2ccccc2)CC1
Temperature: 50 °C
Yield: 53.6 %

Procedure:
Dissolve 1-phenyl-cyclopropanecarboxylic acid (2.5 g, 15.4 mmol) in a mixture of sulfuric acid (12.5 mL) and DCM (25 mL). Add sodium azide (2.3 g, 35.4 mmol) by small portions at ambient temperature. Heat the reaction mixture at 50° C. for 8 h, cool to 0° C. and slowly add 2M aqueous NaOH until pH 11. Extract the reaction mixture with DCM (3×100 mL), combine the organic extracts and dry over anhydrous Na2SO4. Evaporate the solvent and purify by chromatography on silica gel eluting with DCM and DCM/2M ammonia in methanol (9:1) to obtain the title compound as a brown oil (1.1 g, 54%). MS (ES+) m/z: 134 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C(N(CC)CC)C.CN(C)C=O>O>[CH:2]1([O:7][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrC1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reaction time: 16 h
Yield: 49.2 %

Procedure:
A mixture of bromocyclopentane (14.9 g), N-hydroxyphthalimide (16.3 g), triethylamine (15 ml), and dimethylformamide (30 ml) was stirred for 16 hours, then poured into water (500 ml). The oily mixture was extracted with ethyl acetate, and the combined extracts, after washing (water), drying, and removal of solvent gave a white solid. This solid was recrystallised from ethanol to give N-cyclopentyloxyphthalimide (11.37 g, 49%); m.p. 81.2°-82.5°; νmax. (CHBr3) include 1780, 1720 cm-1 (CO-N-CO), 970 cm-1 (>N-O-<CH); τ values (DMSO-d6) 2.08 (4 Ar-H), 5.12 (cyclopentyl 1-H), 8.18 (4-CH2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9](OCC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:10]
Reactant: CCOC(=O)c1cccc(-c2ccco2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1cccc(-c2ccco2)c1
Yield: 83 %

Procedure:
Ethyl 3-(2-furyl)benzoate [J. Chem. Soc., (B), 1971, 2305 was dissolved in 5 ml of anhydrous ethyl ether. With stirring under ice cooling, 23 mg of lithium aluminium hydride was added The mixture was stirred for 40 minutes. After the reaction, water and ethyl ether were added to extract the reaction mixture The extract was worked up in a customary manner to give 170 mg (yield 83%) of 3-(2-furyl)benzyl alcohol
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13]>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH3:13]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=Nc1c(C)cc(C)cc1C)c1ccccc1
Temperature: 200 °C

Procedure:
2,4,6-Trimethylaniline (11.5 mL, 82 mmol, Aldrich) was mixed with propiophenone (10 mL, 74.5 mmol, Aldrich) and TSOH (1.4 g, 7.3 mmol, Aldrich). The resulting mixture was heated for 2 h at 200° C. under a weak stream of Ar to remove formed H2O. After cooling to RT the reaction mixture was poured into hexanes (100 mL), filtered, and the precipitate washed with additional hexanes (2×100 mL) followed by the evaporation of the filtrate. The residue was filtered through a 9×4.1 cm plug of silica gel in hexanes/ether 10/1 (300 mL collected). After evaporation of the solvent the unreacted starting materials were distilled off under vacuum (45–50° C./53 Pa). The residue was crystallized from methanol at −30° C. Product was isolated as large orange-yellow crystals, 4.8 g, (25.6%). 1H NMR (CDCl3) 8.00–7.94 (m, 2H); 7.51–7.45 (m, 3H); 6.89 (s, 2H); 2.50 (q, 2H; J=7.7 Hz); 2.31 (s, 3H); 2.04 (s, 6H); 0.98 (t, 3H; J=7.7 Hz). 13C NMR (CDCl3): 170.8, 146.4, 138.2, 131.9, 130.3, 128.7, 128.6, 127.7, 125.6, 23.9, 20.9, 18.2, 11.6. Anal. Calcd for C18H21N: C, 86.00; H, 8.42; N, 5.57. Found: C, 85.79; H, 8.41; N, 5.56.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[N:32]2[N:33]=[C:34]([SH:36])[N:35]=[C:31]2[N:30]=[CH:29][CH:28]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:36][C:34]3[N:35]=[C:31]4[N:30]=[CH:29][CH:28]=[C:27]([CH3:26])[N:32]4[N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cc1ccnc2nc(S)nn12
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4nccc(C)n4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 7-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) d 1.53-1.73 (m, 8H) 2.14 (m, 1H) 2.24 (m, 1H) 2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.62 (m, 1H) 2.80 (d, J=17.9 Hz, 1H) 2.96 (d, J=20.0 Hz, 1H) 3.80 (s, 3H) 7.03 (d, J=8.2 Hz, 1H) 7.15 (d, J=4.7 Hz, 1H) 7.22 (dd, J=8.4, 2.06 Hz, 1H) 7.29 (d, J=1.9 Hz, 1H) 8.63 (d, J=4.7 Hz, 1H). MS (APCI) calcd for C25H27ClN4O4S; 515.03; found M=515.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 85 °C
Yield: 99 %

Procedure:
1,2-Difluoro-4-nitrobenzene (8.0 g, 50 mmol) was added to morpholine (4.85 g, 55.7 mmol) and anhydrous potassium carbonate (3.85 g, 27.9 mmol) in acetonitrile (75 ml). The reaction was heated at 85° C. for 3 hours, cooled, filtered and the solid washed with EtOAc (50 ml). Evaporation of the filtrate, trituration with isohexane and filtration gave the title compound as a solid (11.2 g, 98%). NMR (CDCl3): 3.28 (t, 4H), 3.88 (t, 4H), 6.92 (t, 1H), 7.92 (dd, 1H), 8.00 (m, 1H); m/z 227.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24]1([CH2:30][CH:31]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.OP([O-])(O)=O.[K+]>CO>[CH2:15]([NH:23][CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CO
Product: c1ccc(CCNCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodiumtriacetoxyborohydride (8.87 g, 41.3 mmol) is added in small portions at 0° C. to a stirred solution of phenethylamine (5.0 g, 41.3 mmol) and phenylacetaldehyde (4.96 g, 41.3 mmol) in methanol (50 ml). The reaction mixture is stirred at rt overnight, poured onto saturated aqueous KH2PO4 solution and extracted twice with EtOAc. The solvent is evaporated, the residue is taken up in 1N HCl and washed twice with dichloromethane. The aqueous layer is adjusted to pH 9 by the addition of ammonium hydroxide solution and extracted with dichloromethane. Drying the combined organic layers over Na2SO4 and evaporating the solvents give crude title compound as a pale yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:22])([F:21])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].Cl>ClCCl>[CH3:24][C:23]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:6]([F:21])([F:22])[F:5])[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:25]
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a mixture of 4.367 kilograms (32.75 moles) of aluminum chloride and 8.8 liters of dichloromethane at 0° C. is added gradually a solution of 3,267 kilograms of 1,4-bis(2,2,2-trifluoroethoxy)benzene and 1.899 kilograms (13.7 moles) of acetic anhydride in 1.3 liters of dichloromethane. The reaction temperature is maintained to 5° to 10° C. while stirring the mixture for about 16 hours. The reaction mixture is then heated to its reflux temperature and maintained under reflux for 4 hours. The reaction mixture is then acidified with 8.76 kilograms of 10 percent hydrochloric acid. Ice is added to the mixture to maintain the temperature below 20° C. The organic layer is separated and the aqueous layers are extracted several times with dichloromethane. The organic layers are dried, then evaporated to provide a residue which is triturated with hexane to provide a yellow solid product. Two crops of product are obtained providing a total yield of 3.088 kilograms of 2,5 -bis(2,2,2trifluoroethoxy)acetophenone, m.p. 84° to 88° C., yield 82 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.[N:33]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH2:47])=[N+:34]=[N-:35]>C(Cl)(Cl)Cl.C(Cl)Cl>[N:33]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)(=[O:22])=[O:21])=[N+:34]=[N-:35]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Reaction time: 8 h

Procedure:
To a solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (intermediate 1.6) (600 mg, 1.41 mmol) in chloroform (2.82 mL) was added DIEA (545.7 mg, 4.24 mmol) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (616.3 mg, 2.82 mmol). The reaction was stirred overnight at which point the mixture was diluted with 50 mL DCM and washed with NaHCO3 (50 mL). The aqueous layer was extracted with DCM (2×50 mL) and the combined organic fractions washed with water (200 mL), brine (200 mL), and dried over Na2SO4. Removing the solvent gave the title compound as an oil which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCC3(CC2)OCCO3)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
8-(Pyridin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (7.0 g, 31.8 mmol, 1.0 eq.) was dissolved at 0° C. in conc. HCl (42 ml) and stirred for 14 hours at RT. After monitoring by TLC, the reaction solution was rendered alkaline with 2 M NaOH solution and extracted with chloroform (250 ml). The org. phase was dried over sodium sulfate and concentrated under reduced pressure. Yield: 80% (4.5 g, 25.56 mmol)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>CC(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCC3(CC2)OCCO3)ccn1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCN(c2ccncc2)CC1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
A solution of 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4.5]decane (172 g) in acetone (700 ml) was combined with 4N hydrochloric acid (700 ml) and stirred at 50° C. for 20 minutes. Acetone was distilled off, and the residue was made alkaline by an addition of an aqueous solution of sodium hydroxide, and then extracted with dichloromethane. After drying and concentrating, the resultant residue was crystallized from ether, collected by filtration and dried to obtain the title compound (119 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8].[NH2:37][C:38]1[CH:42]=[CH:41][O:40][N:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>CCCCCCC.C(Cl)Cl.CCOC(C)=O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:37][C:38]4[CH:42]=[CH:41][O:40][N:39]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:36])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[Cl:8]
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
A 100-mL RBF was charged with perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3.0 g, 5.29 mmol) then purged with nitrogen. THF (191 mL) and 3-aminoisoxazole (4.89 g, 5.82 mmol) were introduced and the resultant tan solution cooled to 0° C. A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 11.1 mL, 11.1 mmol) was added dropwise via syringe to the stirred reaction mixture over 5 min. After 15 min, 1.0 N HCl (25 mL) was introduced and the resultant reaction mixture was allowed to warm to RT. The mixture was diluted with and EtOAc (25 mL) and the layers were separated, and the aqueous layer was further extracted with EtOAc (3×25 mL). The combined organic layers were then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (100-g Biotage column, eluent: gradient, 0 to 100% EtOAc in heptane with 10% CH2Cl2 as an additive) to afford 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.97 g, 4.22 mmol, 80% yield) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ=8.62 (d, J=2.3 Hz, 1H), 8.47 (s, 1H), 8.28 (d, J=9.6 Hz, 1H), 7.94 (dd, J=2.3, 9.1 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.91 (d, J=9.7 Hz, 1H), 3.82 (s, 3H). m/z (ESI) 468.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[OH:13])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(c1ccc(F)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 88.1 %

Procedure:
212 g (1 mol) of p-fluorotrifluoroacetophenone is dissolved in 1000 ml of ethanol; to the solution at 0°-10° is added 20 g of NaBH4, and the whole is stirred for 2 hours, and then for a further 4 hours at room temperature. 500 ml of water is slowly added, and the supernatant clear solution is decanted, and subsequently concentrated in a rotary evaporator. The residue is dissolved in diethyl ether, the solution is washed with water, dried with sodium sulfate and concentrated by evaporation. The oily residue is fractionally distilled to yield 171 g of p-fluorophenyl-trifluoromethyl carbinol, b.p. 86°-90° C./20 mbars.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([NH2:27])=[C:22]([NH2:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.[CH3:37][O:38][C:39](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]4[NH:27][C:37]([O:38][CH3:39])=[N:28][C:22]=4[CH:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: COC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]c(OC)nc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 1.00 g (2.02 mmol) (R)-2-(3,4-diamino-5-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 4a), 2.0 mL (15.0 mmol) tetramethoxymethane and 40 mg p-toluenesulphonic acid-monohydrate in 20 mL MeOH was refluxed for 1 h. The mixture was evaporated down i.vac. and the residue was purified by chromatography (Alox, activity stage II-III, DCM/MeOH 20:1).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C(OCC)(=O)C>[CH3:14][S:15]([O:6][CH2:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:17])=[O:16]
Reactant: OCCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)OCCC1CC1

Procedure:
A 0.5 g quantity of 2-cyclopropylethanol and 3.1 ml of triethylamine were dissolved in 10 ml of ethyl acetate, and 0.75 ml of methanesulfonyl chloride was added with ice-cooling and stirring. After stirring for 30 minutes, water was added to the reaction mixture and extraction was performed. The organic layer was washed with water twice and concentrated by removing the solvent under reduced pressure to give 1 g of pale yellow oily 2-cyclopropylethyl methanesulfonate.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
Combine 4-cyanobenzoic acid (30 mg, 2.07 mmol), tert-butylamine (0.5 mL, 4.13 mmol), triethylamine (0.4 mL, 2.89 mmol), and HATU (1.1 g, 2.89 mmol) in anhydrous DMF (7 mL). Stir at ambient temperature for 17 h. Partition the reaction mixture between brine (15 mL) and diethyl ether (15 mL), separate the organic layer, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (0.4 g, 89%). MS (ES+) m/z: 203 (M+H)+.