Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH3:10][CH2:11]OCC.C1(C)C=CC=CC=1.C([Mg]Cl)C>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=Cc1ccc(Br)nc1
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(O)c1ccc(Br)nc1
Reaction time: 4 h

Procedure:
To a chilled (ice bath) solution of 6-bromo-pyridine-3-carbaldehyde (15.0 g, 80.64 mmol) in a 1:1 mixture of ether:toluene (400 mL) was added a 2 M solution of ethylmagnesium chloride (40.0 mL, 80.0 mmol) in THF over a 15 minute period. The reaction was monitored by TLC (ethyl acetate-hexanes 3:7). After 4 hours, the mixture was diluted with saturated aqueous ammonium chloride (300 mL) and the organic phase separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was passed through a pad of silica gel eluting with dichloromethane-hexanes (0-100%). The material from the pad was purified by silica gel chromatography eluting with ethyl acetate-hexanes (2:98, then 4:96, then 6:94, then 8:92, then 1:9, then 12:88, then 15:85) to afford 1-(6-bromo-pyridin-3-yl)-propan-1-ol as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Reactant: CNC
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
(3-Nitrophenyl)methanesulfonyl chloride (2.36 g, 10 mmol) was dissolved in benzene (30 mL), then to this solution was added 40% aqueous dimethylamine (12.6 mL, 0.1 mol) and the reaction mixture was vigorously stirred for 2 h at room temperature. The benzene layer was separated and the aqueous layer extracted with CH2Cl2 (2×25 mL). The recombined organic layers were washed with saturated aqueous NaHCO3 (30 mL), water (30 mL) and the solvent removed under reduced pressure to give 2.32 g (95%) of (3-nitrophenyl)-N,N-dimethylmethanesulfonamide as crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]#[N:17])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]1[NH:22][N:21]=[N:20][N:17]=1)=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2[nH]c(=O)c(C#N)cc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc2[nH]c(=O)c(-c3nnn[nH]3)cc2c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
6-tert-Butyl-3-cyano-1,2-dihydroquinolin-2-one (1.74 g, 7.7 mmol) was dissolved in DMF (20 ml), and ammonium chloride (1.65 g, 30.8 mol) and sodium azide (2.00 g, 30.8 mol) were added to the resultant mixture. The mixture was stirred at a bath temperature of 120° C. for 16 hours. Water added to the reaction mixture. After removal of the precipitates by filtration, the reaction mixture was recrystallized from DMF-methanol. The crystals that precipitated were collected, to thereby obtain the title compound as yellow powder (1.08 g, 4.0 mmol, 52%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].COCCOC>O>[N:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=3[CH:12]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1COc2ccc(-c3ccncc3)cc2N1
Yield: 42.7 %

Procedure:
A mixture of 6-bromo-4H-benzo[1,4]oxazin-3-one [N. Mazharuddin et al., Indian J. Chem. 1969, 7, 658] (1.37 g. 6 mmol), pyridine-4-boronic acid (0.72 g, 6 mmol), sodium bicarbonate (1.51 g, 18 mmol), (tetrakis-triphenylphosphine)palladium (0) (348 mg, 0.3 mmol) in water (18 mL), and 1,2-dimethoxyethane (30 mL), was stirred at reflux under an argon atmosphere for 72 h. Reaction mixture was cooled and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and dried (Na2SO4) and evaporated in vacuo to give a brown solid which was purified by chromatography on silica gel (30 g) eluting with 0-5% MeOH in EtOAc to give the title compound (0.58 g, 43%) as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=1[O:19][CH3:20])(=[O:9])[CH3:8].N#N.[O:23]=[C:24](Cl)OC(Cl)(Cl)Cl.ClC(C1NCCS1)=O.CCN(CC)CC>C(Cl)Cl>[S:1]=[C:2]1[N:6]([C:24]([O:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:7](=[O:9])[CH3:8])=[C:12]([O:19][CH3:20])[CH:13]=2)=[O:23])[CH2:5][CH2:4][S:3]1
Reactant: COc1cc(CO)ccc1OC(C)=O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: SC1=NCCS1
Agent: N#N
Agent: O=C(Cl)C1NCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Temperature: 25 °C
Yield: 36.9 %

Procedure:
To a flask purged with N2 was added 2-mercaptothiazoline (MTA) (167 mg, 1.1×1.27 mmol) and polyvinyl pyridine (PVP) (159 mg, 8.8 mg/eq, 1.1×1.27 mmol) (see Scheme 1). Seven mL of dry CH2Cl2 (5 mL/mmol MTA) were added to the flask while maintaining a positive N2 pressure. The suspension was stirred at room temperature, and diphosgene (137 mg, 85 μL, 0.55×1.27 mmol) was added dropwise. After being stirred for five hours the intermediate chloroformylthiazolidine (VI) was filtered through a sintered glass filter into a flask containing the benzyl alcohol, I, (250 mg, 1.27 mmol) dissolved in 1-2 mL of dry CH2Cl2. The beads of PVP thus removed were rinsed in portions with a total of 5 mL of fresh, dry CH2Cl2. The flask containing the filtrate was placed under a positive N2 pressure and immersed in an ice bath. To the cooled solution was added NEt3 (141 mg, 195 μL, 1.1×1.27 mmol) directly into the stirred solution, via syringe. After stirring overnight the diluted reaction solution was extracted with 1N HCl, water and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified twice by column chromatography on silica gel eluting with dichloromethane/methanol (98:2, v/v) to give 160 mg (37%) of VII as a nearly pure yellow solid (compound appears to decompose slightly while on the column); Rf=−0.62 (dichloromethane/methanol, 98:2, v/v); 1HNMR (CDCl3) δ 7.11 (d, 4J=1.65 Hz, 1H), 7.01-6.99 (m, 1H), 6.98-6.95 (m, 1H), 5.27 (s, 2H), 4.52 (t, 3J=7.5 Hz), 3.82 (s, 3H), 3.29 (t, 3J=7.5 Hz, 2H) and 2.30 (s, 3H). Exact mass (ESI) calculated for C14H15NNaO5S2 [M+Na] 364.0284. found 364.0277.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][NH:5][C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[H][H]>C(O)C.[Pd]>[NH2:16][C:15]1[C:6]([NH:5][CH2:4][CH:3]([O:19][CH3:20])[O:2][CH3:1])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCC(OC)OC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1NCC(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To an argon purged solution of methyl 2-(2,2-dimethoxyethylamino)-3-nitrobenzoate (1.4 g, 4.7 mmol) from Step B above in ethanol (50 mL) at room temperature was added 10% palladium on carbon. A hydrogen balloon was then attached and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through celite and concentrated under reduced pressure to give methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (1.2 g, quantitative yield) as a dark red oil: 1H NMR (300 MHz, DMSO-d6) δ 7.06 (d, J=5.0 Hz, 1H), 6.85 (dd, J=7.8, 1.2 Hz, 1H), 6.74 (t, J=7.8 Hz, 1H), 6.06 (t, J=7.5 Hz, 1H), 4.84 (s, 2H), 4.38 (t, J=5.4 Hz, 1H), 3.80 (s, 3H), 3.23 (s, 6H), 3.04 (dd, J=7.2, 5.7 Hz, 2H); MS (ESI+) m/z 254 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9](C(O)=O)([CH2:10]3)[CH2:8]2.OS(O)(=O)=O.[N-:24]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:24][C:9]12[CH2:10][CH:11]3[CH2:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])([CH2:14][CH:13]1[CH2:12]3)[CH2:8]2
Reactant: O=C1CCCN1C12CC3CC(C1)C(C(=O)O)(C3)C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC12CC3CC1CC(N1CCCC1=O)(C3)C2
Temperature: 45 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a stirred solution of the acid obtained in step II (0.5 g, 2.0 mmol) in CHCl3 (21 mL) at room temperature was added conc. H2SO4 (1.0 mL, 20 mmol) followed by NaN3 (0.39 g, 6.0 mmol) in portions over a period of 30 min., so that the temperature of the reaction did not rise above 40° C. The reaction was warmed to 45° C. and stirred for 2 h, then cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-(3-aminotricyclo[3.3.1.03,7]non-1-yl) pyrrolidin-2-one as an off-white solid (0.25 g) in 74% yield. m/z (M+1) 221; 1H NMR (CDCl3) 300 MHz δ 3.41 (t, J=7.0 Hz, 2H), 2.46 (dd, J=2.4, 10.3 Hz, 1H), 2.38-2.28 (m, 1H), 2.30 (t, J=8.3 Hz, 2H), 2.16-1.82 (m, 9H), 1.78 (dd J=2.6, 10.8 Hz, 1H), 1.66-1.58 (m, 1H), 1.51 (dd, J=2.5, 10.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.[F-].[K+].CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:27]1([NH:31][C:2]2[N:7]=[C:6]3[CH:8]=[N:9][CH:10]=[CH:11][C:5]3=[N:4][C:3]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH2:14][CH2:13]2)[CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCC1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
Combined 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (0.7226 g, 1.923 mmol), cyclobutanamine (0.493 mL, 5.77 mmol), and potassium fluoride (0.145 g, 2.500 mmol) in DMSO (7.2 mL) and DIPEA (0.670 mL, 3.85 mmol) at 23° C. The reaction was stirred at 23° C. for 16 hr and diluted with water (30 mL) to furnish a yellow-orange suspension. The resulting solid was filtered, rinsed with water, and dried in vacuo to give the title compound (0.62 g, 79%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.68-1.77 (m, 2H), 2.12 (quind, J=9.3, 2.7 Hz, 2H), 2.27-2.35 (m, 2H), 2.56-2.68 (m, 4H), 3.35-3.42 (m, 4H), 3.60 (s, 2H), 4.57 (sextet, J=8.0 Hz, 1H), 6.98 (d, J=7.3 Hz, 1H), 7.06-7.12 (m, 1H), 7.22 (td, J=9.9, 2.7 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H), 7.46-7.53 (m, 1H), 8.27 (d, J=5.4 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z [M+H]+ 411.0.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]([CH:12]([CH3:14])[CH3:13])[S:8](=[O:11])(=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][N:9]1[C:4]2[CH:3]=[C:2]([F:1])[CH:16]=[CH:15][C:5]=2[CH2:6][N:7]([CH:12]([CH3:14])[CH3:13])[S:8]1(=[O:11])=[O:10]
Reactant: CC(C)N1Cc2ccc(F)cc2NS1(=O)=O
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1Cc2ccc(F)cc2N(CCCl)S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(1.48 g, 6.07 mmol) in dry DMF (15 ml) was added via a cannula to a flask containing sodium hydride (175 mg, 7.28 mmol) and DMF (2 ml) in Argon atmosphere, and stirred for 2 hours at room temperature when 1-bromo-2-chloroethane (7.28 mmol, 605 μl) was added dropwise. The mixture was stirred overnight at room temperature and water (75 ml) added. The product was extracted with EtOAc (3×50 ml) and the combined organic extracts were washed with water (1×100 ml) and then brine (1×100 ml), dried over sodium sulphate and solvent evaporated at reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc:Hexanes 1:4) affording pure 1-(2-chloroethyl)-3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(SC2C=CC=CC=2C(O)=O)C=CC=CC=1.S(Cl)(Cl)=O.[CH3:37][NH:38][CH3:39]>C1C=CC=CC=1>[CH3:37][N:38]([CH3:39])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1Sc1ccccc1
Reactant: CNC
Agent: O=C(O)c1ccccc1Sc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)C(=O)c1ccccc1Sc1ccccc1

Procedure:
Following the procedure described in Example 1, 2-(phenylthio)benzoyl chloride is prepared from 0.065 mole of 2-(phenylthio)benzoic acid and excess thionyl chloride. A solution of the oily acid chloride in 50 ml. of benzene is added dropwise with stirring to a solution of 7 g. of dimethylamine in 50 ml. of benzene. The mixture is heated briefly to refluxing. Evaporation of the solvent under reduced pressure leaves N,N-dimethyl-2-(phenylthio)benzamide as the residue.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([C:12]1[S:16][C:15]([C:17]([O-:19])=[O:18])=[C:14]2[CH2:20][CH2:21][CH2:22][CH2:23][C:13]=12)(=[O:11])[CH3:10].[Cl:24][C:25]1[CH:26]=[C:27]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1>C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]([C:32]([OH:37])([C:33]([F:34])([F:35])[F:36])[CH2:10][C:9]([C:12]2[S:16][C:15]([C:17]([O:19][CH3:2])=[O:18])=[C:14]3[CH2:20][CH2:21][CH2:22][CH2:23][C:13]=23)=[O:11])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: CC(=O)c1sc(C(=O)[O-])c2c1CCCC2
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)c2c1CCCC2
Reaction time: 1.5 h
Yield: 607.9 %

Procedure:
Add a solution of LDA (2M in THF, 19.5 mL, 3.89 mmol) to a suspension of 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (7.4 g, 3.11 mmol) in dry THF (80 mL) at −78° C. under N2. After stirring for 1.5 h, add 1-(3,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone (9.9 g, 3.73 mmol) to the reaction mixture and stir the resultant mixture at the same temperature for additional 2 hours. Quench the reaction with saturated NH4Cl aqueous solution. Extract the aqueous mixture with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 50:1) to afford methyl 3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate as an orange solid (9.1 g, 60.4%). MS (m/z): 481 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][NH:12]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])[CH:3]=1.Cl[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:12]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:13]=[C:14]([OH:16])[CH2:15]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:22][CH2:23]2)[CH3:20])[CH:3]=1
Reactant: Clc1cccnc1Cl
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(O)=NN1c1ncccc1Cl)C1CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 87.3 %

Procedure:
1.0 g of N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-5-oxopyrazolidine-3-carboxamide was dissolved in 10 mL of N,N-dimethylformamide, and 460 mg of 2,3-dichloropyridine and then 350 mg of sodium hydride were added, followed by stirring at about 70° C. for about 7 hours in a nitrogen atmosphere, and then the reaction liquid was left to cool. To the reaction liquid, water and ethyl acetate were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/ethanol=9/1) to obtain 1.15 g of the desired product (melting point: 165-167° C.).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](SC)=[N:10]2.O[O:25][S:26]([O-:28])=O.[K+].[CH3:30]O>O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:26]([CH3:30])(=[O:28])=[O:25])=[N:10]2
Reactant: COc1ccc2nc(SC)ccc2c1Oc1ccc(F)cc1F
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A solution of 0.25 g of 5-(2,4-difluoro-phenoxy)-6-methoxy-2-methylsulfanyl-quinoline in 10 mL of methanol was treated with aqueous OXONE™ solution (1.3 g in 5 mL H2O) and stirred for 2 hours at room temperature. The reaction mixture was partitioned between water and dichloromethane, the organic layer was dried (MgSO4), and the solvent was removed under vacuum. The solid residue was dissolved in a minimum amount of dichloromethane and washed through a silica gel plug to remove the baseline impurities. Elution with 30% EtOAc/hexane yielded 0.11 g (38%) of 5-(2,4-difluoro-phenoxy)-2-methanesulfonyl-6-methoxy-quinoline 701 ([M+H]+)=366, as white crystals.
Reaction SMILES: N1C2C(=CC=C([C@H]3[C@@]4(C5C(=CC=CC=5)NC4=O)C3)C=2)C=N1.C([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C@H:38]3[C@@:40]4([C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[N:42]([CH3:49])[C:41]4=[O:50])[CH2:39]3)[CH:36]=2)[CH:31]=[N:30]1)C1C=CC=CC=1>>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C@H:38]3[C@@:40]4([C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[N:42]([CH3:49])[C:41]4=[O:50])[CH2:39]3)[CH:36]=2)[CH:31]=[N:30]1
Reactant: CN1C(=O)[C@@]2(C[C@H]2c2ccc3cnn(Cc4ccccc4)c3c2)c2ccccc21
Agent: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2cn[nH]c2c1
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3cn[nH]c3c2)c2ccccc21
Yield: 74.1 %

Procedure:
Method 1 (Bn): The title compound was prepared in a manner similar to the method of (1R,2S)-2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (1R,2S)-2-(1-benzyl-1H-indazol-6-yl)-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (1.16 g, 3.06 mmol). Purification via column chromatography (silica gel, 3-6% MeOH in CH2Cl2) yielded the title compound as a pale-yellow solid (656 mg, 74%); 1H NMR (400 MHz, CDCl3) δ 10.06 (br. s, 1H), 8.05 (s, 1H), 7.64 (d, 1H, J=7.6 Hz), 7.36 (s, 1H), 7.14 (t, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.62 (t, J=7.6 Hz, 1H), 5.91 (d, J=7.9 Hz, 1H), 3.46 (t, J=7.8 Hz, 1H), 3.34 (s, 3H), 2.26-2.23 (m, 1H), 2.08-2.04 (m, 1H); MS ESI 290.1 [M+H]+, calcd for [C18H15N3O+H]+ 290.13.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1OCCN1CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.8 %

Procedure:
To an ice cold stirring solution of crude 3-(2-hydroxy-ethyl)oxazolidin-2-one (15.1 g, 115 mmol) in dichloromethane (40 mL) was added triethylamine (18 mL, 129 mmol), and 4-(N,N-dimethylamino)pyridine (0.143 g, 1.2 mmol). A slurry of 4-toluenesulfonyl chloride (25.0 g, 131 mmol) in dichloromethane (50 mL) was then added dropwise. The reaction mixture was stirred for 3 d at room temperature, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was slurried in isopropanol and filtered to give 23.88 g (73%) of a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][Si](C(C)(C)C)(C)C)=[C:16]([CH2:28][CH:29]=[CH2:30])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:28][CH:29]=[CH2:30])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1
Reactant: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1.519 g (3.48 mmol) of the product of Step F in 8.0 mL of anhydrous THF was added 3.6 mL of a 1.0M solution of tetra-n-butylammonium fluoride in THF and the reaction mixture was stirred for 2.5 hours at room temperature. The reaction mixture was then evaporated in vacuo and the residual oil was chromatographed on a silica gel flash chromatography column eluted with ethyl acetate. The purified fractions were combined, evaporated and dried in vacuo to afford the title compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CS(=O)(=O)CCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccn1
Yield: 65 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and 2-(methylsulfonyl)ethyl chloroformate. Yield: 65% of theory, C31H35N7O7S (649.7); Rf value: 0.54 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=650; (M+H+Na)++=336.6; (M+Na)+=672; (M+2Na)++=347.6.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20]Br>C(#N)C>[Br:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: BrCCBr
Reactant: NC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1c(O)cccc1OCCBr

Procedure:
A mixture of 23.0 g of 2,6-dihydroxybenzamide, 20.7 g of potassium carbonate and 28.2 g of 1,2-dibromoethane in 300 ml of acetonitrile is stirred under reflux for 2-3 hours. The reaction mixture is filtered whilst still warm, the filtrate is evaporated and the residue is recrystallised from a little methanol. 6-(2-Bromoethoxy)salicylamide with a melting point of 120°-121° is obtained.