Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[C:9]2[O:10][CH2:12][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g, 46 mmol) and BrClCH2 (23.9 g, 185 mmol) in dry DMF (100 mL) was added Cs2CO3 (25 g, 190 mmol). The mixture was stirred at 60° C. overnight and was then poured into water. The resulting mixture was extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 70%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.42 (d, J=0.4 Hz, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.15 (s, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:24]([NH:26][NH2:27])=O>O=P(Cl)(Cl)Cl>[N:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:24]=[N:26][N:27]=[C:7]2[C:6]2[CH:16]=[CH:17][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: NNC=O
Reactant: COc1ccc(C(=O)Nc2ccncc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Oc1ccc(-c2nncn2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a solution of 4-Methoxy-N-pyridin-4-yl-benzamide (75 mg) in POCl3 (3 ml) was added PCl5 (68 mg) and the reaction mixture heated at reflux for 5 h. The reaction mixture was concentrated and dissolved in dimethyl formamide (2 ml) and Formic acid hydrazide (5 eq, 100 mg) was added and stirred for 2 h. The reaction mixture was concentrated and diluted with isopropanol (3 mL) and 0.25 ml of conc. HCl was added. The reaction mixture stirred for 18 h, quenched with 1 NaOH, extracted with dichloromethane, dried magnesium sulfate and concentrated. The crude product dissolved in methylene chloride (2 mL) and boron tribromide (0.63 mL 1.0M hexanes) was added at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was quenched with 1 N NaOH and pH adjusted to 9, extracted with dichloromethane, dried magnesium sulfate, filtered and concentrated. Purification via Biotage MPLC chromatography eluting with 0-20% methanol/methylene chloride provided the title compound (32 mg, 55%). MS: (M+H m/z=239.2).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:12]4[CH:24]=[CH:23][S:22][C:13]=4[C:14](=[O:21])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[OH:20])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)C(C)C)(C)C>C(Cl)Cl.C1COCC1>[OH:20][C:19]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:21])[C:13]3[S:22][CH:23]=[CH:24][C:12]=3[C:11]=2[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([CH:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH3:3])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(N)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(NS(C)(=O)=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reaction time: 1.5 h
Yield: 19.5 %

Procedure:
A solution of 9-[4-(1-aminoethyl)phenyl]-8-hydroxythieno[2,3-c]quinolin-4(5H)-one (30 mg, 0.089 mmol) and methanesulfonyl chloride (9.0 μL, 0.11 mmol) in 2:1 methylene chloride/THF (3 mL) was stirred at room temperature for 10 min followed by the addition of N,N-diisopropylethylamine (19 μL, 0.11 mmol). The reaction mixture was stirred for 1.5 h, concentrated and purified by preparatory HPLC (C18 silica, water/acetonitrile w/0.05% TFA gradient) to afford the desired product (7.2 mg, 20%) as an amorphous brown solid: 1H NMR (500 MHz, CD3OD) δ 7.57-7.56 (m, 2H), 7.53 (d, J=5.4 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 7.32-7.30 (m, 2H), 7.16 (d, J=8.9 Hz, 1H), 6.02 (d, J=5.4 Hz, 1H), 4.71 (q, J=4.6 Hz, 1H), 2.82 (s, 3H), 1.62 (d, J=7.0 Hz, 3H); ESI MS m/z 415 [C20H18N2O4S2+H]+; HPLC >99%, tR=10.18 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([I:11])=[C:9](Cl)[N:8]=[C:7]([Cl:13])[N:6]=1)=[O:4].[NH3:14]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([I:11])=[C:9]([NH2:14])[N:8]=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: N
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1I
Solvent: CS(C)=O
Product: COC(=O)c1nc(Cl)nc(N)c1I
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2,6-Dichloro-5-iodopyrimidine-4-carboxylic acid methyl ester (12 g, 36 mmol) was dissolved in dry dimethyl sulfoxide (DMSO; 100 mL) and treated with a stream of ammonia at such a rate when combined with external water bath cooling to keep the temperature in the range of 20-30° C. After 90 min, the ammonia addition was complete and excess ammonia was removed from the mixture by sparging with a stream of nitrogen for 20 min. The mixture was poured into water (200 mL) with stirring and the precipitated product was extracted with ethyl acetate (75 mL) twice. The combined ethyl acetate extracts were washed twice with water (50 mL), once with saturated NaCl solution, dried and evaporated to give the title compound (10 g, 89% yield) that was used without further purification. MS: M/Z=313.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH:12]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: BrCc1ccccc1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C1CCCN(C(=O)OCc2ccccc2)C1Cc1ccccc1
Temperature: 25 °C
Yield: 6.3 %

Procedure:
A stirring solution of N-(benzyloxycarbonyl)-3-piperidone (1000 mg, 4.25 mmol) and pyrrolidine (454 mg, 6.38 mmol, Aldrich) in dry toluene (10 mL) in a round bottom flask fitted with a Dean-Stark trap was refluxed for 4 h. The reaction was conc. in vacuo to a orange oil. The oil was dissolved in dry acetonitrile (10 mL) and then benzyl bromide (800 mg, 4.68 mmol, Aldrich) was added. The reaction was heated to reflux for 16 h and then cooled to room temperature. The reaction was quenched by the addition of 1M HCl (50 mL) and then extracted with EtOAc (4×40 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and conc. in vacuo to an oil. The oil was purified by flash chromatography (SiO2, 7–20% EtOAc in hexanes) to yield 86 mg of the product as a white solid. MS (ESI) 324 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]([NH2:26])=O)=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2].CS(OS(C)(=O)=O)(=O)=O.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]#[N:26])=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 71 %

Procedure:
Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (500 mg), methanesulfonic anhydride (248 mg) as a dehydrating agent and trifluoroacetic acid (0.11 mL) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 340 mg, yield: 71%) by the same method of Example 1.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:25]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:25])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-4-(3-bromo-phenylamino)-7-methoxy-quinazolin-6-ol (0.27 g, 0.7 mmol) (from Example 17, Step D, supra) in acetone (30 mL) was added K2CO3 (0.48 g, 3.5 mmol) and methyl iodide (0.4 g, 2.8 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:3:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine as a yellow solid. (Yield 0.14 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[OH-].[Na+].[CH2:12](O)[CH3:13].Br[CH2:16][CH3:17]>ClCCl>[CH2:16]([O:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[C:3]=1[O:9][CH2:12][CH3:13])[CH3:17]
Reactant: CCO
Reactant: CCBr
Reactant: Oc1cccc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOc1cccc(F)c1OCC
Temperature: 10 °C
Yield: 81 %

Procedure:
To a 500 ml flask were added 38.4 (0.3 mol) of 3-fluorocatechol [H], 12 g (0.3 mol) of sodium hydroxide and 100 ml of ethanol. After cooling to around 10° C., 100 ml of an ethanol solution of 76.3 g (0.7 mol) of bromoethane was slowly added. After the termination of the addition, they were reacted under a reflux temperature for 5 hours. After the termination of the reaction, dichloromethane was added, followed by extraction. The extraction liquid was washed with water and dried, and the solvent was removed by distillation to obtain 45.5 g of 1,2-diethoxy-3-fluorobenzene [G1] as an oily product. The process yield was 81%.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:35]([C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccc(Cl)cc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-bromo-4-[4-(4-chloro-benzyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.051 g, 0.12 mmol) and EtOH (3 ml) was added 4-methoxybenzaldehyde (0.026 g, 0.18 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.50 ml, 0.50 mmol). The reaction mixture was stirred at 70° C. for 18 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 3%) in ethyl acetate/dichloromethane (v:v; 2:3) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.026 g, 42%). 1H-NMR (500 MHz, DMSO-d6) 2.60 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2—C6H4Cl), 3.66 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.1 Hz, 2H) and 8.13 (d, J=8.1 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 7.41 (m, 4H, C6H4Cl), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.37 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1cc(I)c(Br)cn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Clc1ccc(-c2cc(Cl)ncc2Br)cc1
Temperature: 20 °C
Yield: 70.7 %

Procedure:
To a degassed solution of 5-bromo-2-chloro-4-iodopyridine (Ref. Cottet, F. and Schlosser, M. Tetrahedron 60, 11896-11874 (2004)) (2.0 g, 6.3 mmol), 4-chlorophenylboronic acid (1.1 g, 6.9 mmol) and K2CO3 (1.7 g, 12.6 mmol) in 1,2-dimethoxyethane (24 mL) and H20 (8.0 mL) was added Pd(PPh3)4 (0.727 g, 0.63 mmol) under argon at 20° C. The reaction mixture was refluxed for 15 h under argon, then allowed to cool to 20° C. The reaction was quenched by addition of H2O (30 mL) and extracted with EtOAc (50 mL×3). The combined organic was washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallized in EtOH to afford 1.35 g of the title compound as a light beige solid as the first crop. The second crop of the title product (0.44 g) was also isolated by concentrating the mother liquid followed by recrystallization in EtOH. LC/MS (method B): retention time=2.03 min, [M+H]+=301.9.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:19])[CH3:18]>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:19][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CCN
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Product: CCNC1CCc2c(cccc2NC(C)=O)C1

Procedure:
Starting from 2.03 g (0.01 mol) of 5-acetylamino-2-tetralone and 2.45 g (0.03 mol) of ethylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 1.2 g (44.6% of theory) and with a melting point of 351° C. which does not change after recrystallisation from methanol/ether.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.N1C=CC=CC=1.[CH3:14][C:15]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[N:19][N:18]=1)[CH3:16].Cl>[Cl-].[Na+].O.C(Cl)(Cl)Cl>[CH3:16][C:15]([N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5](=[O:7])[CH3:6])([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[N:19][N:18]=1)[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1-c1nnc(C(C)(C)Nc2ccccc2)n1C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N(c1ccccc1)C(C)(C)c1nnc(-c2ccccc2C)n1C
Temperature: 80 °C
Reaction time: 96 h

Procedure:
Acetic anhydride (0.19 ml) and N,N-dimethylaminopyridine (40 mg) were added to a pyridine (10 ml) solution of N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]ethyl}aniline (500 mg), followed by stirring at 80° C. for 4 days. After the reaction solution and chloroform were added to a 1M hydrochloric acid solution, the reaction solution and chloroform were added to brine and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=99:1 to 96:4) and then the resulting solid was washed with ether to obtain 393 mg of N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]ethyl}-N-phenylacetamide (pale yellow solid).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1.O>CC(N(C)C)=O>[Cl:31][C:32]1[CH:33]=[C:34]([S:38]([N:19]2[CH2:18][CH:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]2=[O:28])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4)C(=O)N3c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (0.050 g) in dimethylacetamide (1 ml) under an argon atmosphere was added sodium hydride (55% in mineral oil, 6.3 mg) at 0° C. The mixture was stirred at 0° C. for 30 min. 3-Chlorobenzenesulfonyl chloride was added. The mixture was stirred at 0° C. for 30 min and at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and concentrated. The product was purified by chromatography ((SiO2, cyclohexane=>cyclohexane/ethyl acetate 1:2) to give (RS)-1-(3-chloro-benzenesulfonyl)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-one (0.049 g) as a colorless solid. MS: 552.7 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].C(Cl)Cl.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.N1C=CC=CC=1>O>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[N:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCCN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 24 h

Procedure:
783 mg of 2-(7-hydroxyheptyl)isoindol-1,3-dione was added to 40 mL of DCM, and 800 mg of p-toluenesulfonyl chloride was added. Pyridine was then added dropwise with stirring, and the mixture was stirred overnight. After 24 h, 100 mL of water was added to the reaction system, which was then violently vibrated and isolated. The water layer was extracted with 50 mL of DCM. The organic layers were combined, successively washed with 100 mL of 5% citric acid aqueous solution, 100 mL of saturated sodium carbonate aqueous solution, and 100 mL of saturated sodium chloride aqueous solution, dried over 5 g of MgSO4 for 30 min, and concentrated via a rotary evaporator to obtain an oily liquid.
Reaction SMILES: ON=C[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].P(Cl)(Cl)(Cl)=O.[C:17](#[N:19])[CH3:18]>>[CH3:18][C:17]1[O:11][C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[N:19]=1
Reactant: CC#N
Reactant: ON=Cc1ccc(O)cc1O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc(O)cc2o1

Procedure:
As depicted in Scheme 2 the known compound, for example 4-((hydroxyimino)methyl)benzene-1,3-diol (B), was cyclized with phosphorus oxychloride in acetonitrile, affording the corresponding 2-methylbenzoxazol-6-ol (B1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=[C:10]1C=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:39])=[C:30]([N:33]4[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34]4)[CH:31]=3)[C:26](=[O:40])[C:25]([C:41]([OH:43])=[O:42])=[CH:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:39])=[C:30]([N:33]4[CH2:37][CH2:36][CH:35]([N:38]=[CH:1][C:2]5[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][CH:3]=5)[CH2:34]4)[CH:31]=3)[C:26](=[O:40])[C:25]([C:41]([OH:43])=[O:42])=[CH:24]2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc[nH]1
Reactant: O=Cc1ccccc1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Product: Cc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with with 2-pyrrolecarboxaldehyde and using the acid (1) (R=cyclopropyl) described in Example 19 one can obtain 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-(2-pyrrylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=cyclopropyl, Z=2-pyrrole).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:16]=[C:17]([NH2:19])[S:18][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(N)=S
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Yield: 111.9 %

Procedure:
A suspension of 3-Bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (10 grams, 35 mmol, obtained in above step) and thiourea (3.28 grams, 42 mmol) in isopropanol (100 mL) was refluxed for 1 hour. After completion of reaction, reaction mass was concentrated and resulted crude was triturated with diethyl ether (50 mL), solids were filtered and dried under vacuum to obtain the title compound (10 grams).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>O1CCCC1>[N+:11]([C:10]1[C:9]([CH3:14])=[CH:8][C:4]([C:5]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[O:7])=[CH:3][C:2]=1[CH3:1])([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Reactant: CC(C)(O)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCC(C)(C)O)cc(C)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 88 %

Procedure:
3,5-Dimethyl-4-nitrobenzoic acid (1 g, 5.12 mmol) is suspended in dry tetrahydrofuran (10 mL) and 1,1′-carbonyldiimidazole (0.91 g, 5.64 mmol) is added. The mixture is stirred for 3 hours then 1-amino-2-methyl-propan-2-ol (patent WO2010/84767, 1 g, 11.22 mmol) is added and the mixture stirred for 30 minutes. The solvent is removed, the residue suspended in EtOAc and washed with 0.2 M aqueous HCl solution, saturated sodium bicarbonate solution and brine, dried and the solvent removed under vacuum to give the title compound (Yield 1.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([CH2:12][O:13][CH3:14])[CH3:11].[H][H]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.ClCCl.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][CH:10]([CH2:12][O:13][CH3:14])[CH3:11]
Reactant: COCC(C)=Nc1c(C)cccc1C
Reactant: [H][H]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCC(C)Nc1c(C)cccc1C
Reaction time: 91 h

Procedure:
The general procedure described in Example B1 is repeated, with the following modifications to the reaction conditions: A catalyst solution is prepared consisting of 5.3 mg of [Ir((1,5-cyclooctadien)Cl]2 (0.0079 mmol), 10.2 mg of A (0.017 mmol) and 11.9 mg of tetrabutylammonium iodide (0.032 mmol) in 5 ml of tetrahydrofuran/dichloromethane (1:1). A substrate solution consisting of 1.5 g of N-(2',6'-dimethylphenyl)-1-methoxymethyl-ethylideneamine (7.8 mmol) in 5 ml of tetrahydrofuran is also used. Hydrogenation is carried out with hydrogen under a pressure of 40 bar. The reaction temperature is 30° C. After 91 hours the conversion is 90%, the ee is 59% (R).