Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[CH2:29][O:30][C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCCCC1.C([Li])(CC)C.[CH2:61]([O:68][CH:69]1[CH:74]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:73]([O:83][CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[CH:72]([CH2:91][O:92][CH2:93][C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[O:71][C:70]1=[O:100])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1(C)C=CC=CC=1.O>[CH2:61]([O:68][CH:69]1[CH:74]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:73]([O:83][CH2:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[CH:72]([CH2:91][O:92][CH2:93][C:94]2[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=2)[O:71][C:70]1([C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][C:3]=1[CH2:29][O:30][C:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[OH:100])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: Brc1cc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2cc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Under a nitrogen stream, to a solution of 2-bromo-1,4-bis(trityloxymethyl)benzene (255.3 mg, 0.36 mmol) in toluene (1.5 ml), a cyclohexane solution of sec-butyllithium (0.99 M, 367 μl, 0.36 mmol) was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was added dropwise at −78° C. to a solution of 3,4,5-trisbenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one (140 mg, 0.26 mmol) in toluene (1.5 ml) and the mixture was stirred at the same temperature for 30 minutes. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:5)) to give the titled compound (242 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O>N1C=CC=CC=1>[CH2:7]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Nc1nncs1
Reactant: CCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-octylbenzenesulfonyl chloride (6.06 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.83 g, 10.8 mmol, 55% yield) as a solid, mp 123-124° C.; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7 Hz), 1.36 (m, 10H), 1.59 (m, 2H), 2.63 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.82 (d, 2H, J=8 Hz), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.2, 29.3, 29.4, 31.1, 31.8, 35.9, 126.5, 129.0, 138.1, 142.6, 148.7, 167.3; MS (Q-TOF) Calcd for C16H24N3O2S2 354.1310, found 354.1211 (M+H)+; Calcd for C16H23N3N3O2S2 376.1129, found 376.1154 (M+Na)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([CH:19]=O)[C:8]=3[CH:21]=2)[CH2:3][CH2:2]1.[CH2:36]([NH2:39])[CH2:37][NH2:38].BrN1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>ClCCl>[CH:1]1([C:4]2[C:5]([N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:38][CH2:37][CH2:36][N:39]=4)[C:8]=3[CH:21]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C=O)c3cc2C2CC2)S(C)(=O)=O)cc1
Reactant: NCCN
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C4=NCCN4)c3cc2C2CC2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 90.7 %

Procedure:
To a mixture of Example 1L (7.0 g, 14.18 mmol) in dichloromethane (117 mL) under nitrogen was added ethylenediamine (0.938 g/1.043 mL, 15.60 mmol) dissolved in 2 mL of dichloromethane (2 mL) in 200 μL portions over 7 minutes. The mixture was stirred at room temperature for 4.5 hours. The reaction mixture was immersed in an ice bath and N-bromosuccinimide (2.65 g, 14.89 mmol) and powdered 4 Å molecular sieves (3.63 g) were added over ˜1 minute. The reaction mixture was stirred in the ice bath for 10 minutes, then the ice bath was removed and the reaction mixture was stirred at room temperature for a total of 72 hours. Reaction progress was monitored by LCMS. After each 24 hour period, additional ethylenediamine and N-bromosuccinimide were added followed by continued stirring at room temperature for 64 hours. The resulting slurry was filtered through a pad of diatomaceous earth with dichloromethane (2×100 mL) washes. The combined dichloromethane layers were washed with 10% sodium bicarbonate and 10% sodium chloride and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the organic layer was concentrated in vacuo to an oily residue. The residue is treated with dichloromethane/acetonitrile (4:1, 100 mL), and the solvent was removed in vacuo leaving a tan foamy solid. The foamy solid was stirred for 20 minutes with hexane/ethyl acetate (4:1, 35 mL), filtered and dried in vacuo giving the title compound as a tan solid (6.86 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.[Br:14]Br.Cl.Cl[Sn]Cl>O.C(O)(=O)C>[Br:14][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=2
Reactant: N#Cc1cccc2ccc(O)cc12
Reactant: BrBr
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(Br)cc2ccc(O)cc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 38.4 %

Procedure:
To a mixture of 7-hydroxy-1-naphthonitrile (26.03 g, 154.0 mmol) and glacial acetic acid (400 mL) was added bromine (51.8 g, 323 mmol). The mixture was stirred at 100° C. for 6 hr. HCl (400 mL of 12 N solution) and SnCl2 (69 g, 308 mmol) were added and the mixture was stirred at 100° C. for 1 hour. The resulting solution was cooled to room temperature and poured into water (1 I). The resulting yellow precipitate was collected by filtration, dried under vacuum, and triturated with ethyl acetate to yield 14.68 g (38%) of the title compound as an off-white solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 222–224° C.;1H NMR (DMSO-d6): δ 7.28–7.35 (2H, m), 7.97 (1H, d, J=8.73 Hz), 8.26 (1H, s), 8.47 (1H, s), 10.65 (1H, s); MS (ESI) m/z 246/247 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of benzenesulfonyl chloride (66 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide (113 mg, 79.3%) as a white solid. MS (ESI+APCI) M+1=461.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](O[CH:9]=[CH:10][C:11]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[N:6][C:5]=2[CH:4]=1.C[O:22][C:23]1C=CC2SC3C(=CC=CC=3SC)N(C(=O)C)C=2[CH:24]=1.[CH2:42]([OH:44])C>OO>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:11]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:10][CH2:9][C:42](=[O:44])[C:7]=3[N:6]([C:23](=[O:22])[CH3:24])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)N(C(C)=O)c1cccc(SC)c1S2
Reactant: COc1ccc2c(c1)N=C1OC=CC(S(C)(=O)=O)=C1S2
Reactant: CCO
Agent: OO
Product: COc1ccc2c(c1)N(C(C)=O)C1=C(S2)C(S(C)(=O)=O)=CCC1=O

Procedure:
2-Methoxy-6-methylsulphonyl-9-oxaphenothiazine (m.p. higher than 280°C.; 48 g.) is prepared by oxidation of 2-methoxy-6-methylthio-10-acetylphenothiazine (m.p. 106°-108°C.; 55.0 g.) dissolved in 95% ethanol (95 cc.) by means of 130 volumes hydrogen peroxide (842 cc.). The crude 2-methoxy-6-methylsulphonyl-9-oxo-10-acetylphenothiazine obtained (m.p. about 160°C.) is saponified by means of an alcoholic solution of potassium hydroxide (11.2 g.) in ethanol (200 cc.).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[S:11](Cl)(Cl)=[O:12].[CH:15]([NH:18][P:19](=[S:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([CH3:17])[CH3:16]>N1C=CC=CC=1>[CH2:21]([O:20][P:19]([N:18]([CH:15]([CH3:17])[CH3:16])[S:11]([CH2:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4])=[O:12])([O:23][CH2:24][CH3:25])=[S:26])[CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CCOP(=S)(NC(C)C)OCC
Reactant: CNC(=O)ON=C(C)SC
Solvent: c1ccncc1
Product: CCOP(=S)(OCC)N(C(C)C)S(=O)CNC(=O)ON=C(C)SC

Procedure:
Methyl N-[[[[[(diethoxyphosphinothioyl)isopropylamino]sulfinyl]methylamino]carbonyl]oxy]ethanimidothioate was prepared by the procedure employed in Example 9, by reacting methyl N-[[(methylamino)carbonyl]oxy]ethanimidothioate (2.43 g, 0.015 mole), thionyl chloride (1.79 g, 0.015 mole), and O,O-diethyl isopropylphosphoramidothioate (3.17 g, 0.015 mole) in pyridine (10 ml). Recrystallization from cyclohexane afforded 1.73 g of colorless prisms of the formula below, mp 53~54°. ##STR27##
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:22])=[N:11]2)=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[N:23]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:22])=[N:11]2)=[CH:6][CH:5]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nn(-c2ccc(CCCl)cc2)c(C)c1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(CCN=[N+]=[N-])cc2)c(C)c1-c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a stirred solution of 1-[4-(2-chloroethyl)phenyl]-3,5-dimethyl-4-phenyl-1H-pyrazole (step 1, 0.34 mmol) and KI (56 mg, 0.34 mmol) in N,N-dimethylformamide (2.7 mL) was added sodium azide (44 mg, 0.68 mmol), and then the resulting mixture was stirred for 6 h at 100° C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate/toluene (4:1). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 87 mg (81%) of the title compound as yellow oil: 1H-NMR (CDCl3) δ 7.46-7.29 (9H, m), 3.55 (2H, t, J=7.3 Hz), 2.96 (2H, t, J=7.1 Hz), 2.34 (3H, s), 2.30 (3H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]2([CH3:25])[NH:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(Br)Br.[OH-:29].[K+].[CH3:31][N:32]([CH3:35])[CH:33]=[O:34]>>[CH2:31]([N:32]1[C:35](=[O:29])[C:18]([CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=2)([CH3:19])[NH:22][C:33]1=[O:34])[N:20]1[C:19](=[O:24])[C:18]([CH3:25])([CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)[NH:22][C:21]1=[O:23]
Reactant: CC1(CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)NC(=O)NC1=O
Reactant: [OH-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: BrCBr
Product: CC1(CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)NC(=O)N(CN2C(=O)NC(C)(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)C1=O
Reaction time: 16 h

Procedure:
34.6 g (0.1 mol) of 5-(3',5'-di-tert.-butyl-4'-hydroxyphenylethyl)-5-methyl-hydantoin, 8.7 g (0.05 mol) of methylene bromide and 38 g (0.1 mol) of potassium hydroxide are initially introduced into 100 ml of dimethylformamide and the mixture is kept at 80° C for 16 hours, whilst stirring. After cooling, insoluble matter is filtered off, first 100 ml of toluene and then 100 ml of water are added and the toluene phase is separated off and repeatedly washed with water. Thereafter, 50 ml of toluene are distilled off under reduced pressure and the residual brown solution is left to stand for 24 hours at room temperature. The resulting precipitate is filtered off and recrystallised from acetonitrile.3,3'-methylene-bis[5-(3",5"-di-tert.-butyl-4"-hydroxy-phenylethyl)-5-methyl-hydantoin] of melting point 222° C (stabiliser No. 20) are thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]2[CH2:14][C:15]3[C:20]([CH:9]12)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OC(N(C)C)N(C)C)(C)(C)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])/[C:11](=[CH:6]\[N:8]([CH3:12])[CH3:9])/[CH:10]2[CH2:14][C:15]3[C:20]([CH:9]12)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3ccccc3C21
Agent: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)/C=C1\C(=O)N(C(=O)OC(C)(C)C)C2c3ccccc3CC12
Yield: 197.5 %

Procedure:
A solution of the 2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester F1 (160 mg, 0.586 mmol) in tert-butoxybis(dimethylamino)methane was heated at 75° C. for 4 h. The solution was diluted with ethyl acetate and washed with water, brine, dried and concentrated to give 3-[1-dimethylamino-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester E1 (colourless solid, 190 mg, 98%). C19H24N2O3; MW: 328.41; LCMS (method A) RT 1.78 min; ES: 329 (MH+), 273; 1H NMR (400 MHz, CDCl3) δ 7.74 (1H, d), 7.15-7.26 (4H, m), 5.61 (1H, d), 3.99 (1H, td), 3.37 (1H, dd), 3.10 (6H, s), 3.06 (1H, dd), 1.60 (9H, s) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(O)COCCO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: NCCCCO
Solvent: OCCOCCO
Product: Cc1ccccc1N1CCc2c(NCCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.6 mmol) was dissolved in diethylene glycol(10 ml) and hereto was added 4-amino-1-butanol(1.0 ml), then reacted at the same condition of Step 5 in the Example 1 to obtain 510 mg of desired compound as solid in 73% of yield.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH:18]([NH:22][CH:23]([CH2:25][CH3:26])[CH3:24])([CH2:20][CH3:21])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.CCOCC>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[CH2:2][N:22]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:18]([CH2:20][CH3:21])[CH3:19]
Reactant: CCC(C)NC(C)CC
Reactant: O=C(CCl)c1cccn1Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: CCC(C)N(CC(=O)c1cccn1Cc1ccccc1F)C(C)CC
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 16.0 g of 2-chloroacetyl-1-(o-fluorobenzyl)pyrrole, Example 1a, 8.3 g of di-sec-butylamine and 20.0 g of potassium carbonate in 250 ml xylene is stirred at 120° C for 72 hours. The mixture is cooled, washed with water, dried and filtered and the xylene is evaporated leaving a brown oil. The oil is dissolved in ether and extracted into a 2N hydrogen chloride solution. The aqueous acidic solution is basified with a sodium carbonate solution and extracted with ether. The ether solution is washed, dried and filtered and the ether removed leaving a brown oil of 1-(o-fluorobenzyl)-2[(di-sec-butylamino)acetyl]pyrrole. Infrared and nuclear magnetic resonance spectra confirm this structure.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]1[C:12]([OH:14])=[O:13].[OH-].[Na+].Cl>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)C1C=Nc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-amino-3-alkyl/3,3dialkyl/3,5-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and enantiomers were prepared by hydrolysis of racemic or optically active 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-{4-benzyloxycarbonylamino/t-butyloxycarbonylamino/ethoxycarbonylamino-3-alkyl/3,3-dialkyl/3,5-dialkyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid with aqueous alkali preferably aqueous sodium hydroxide or inorganic acid such as hydrochloric acid at ambient temperature for 2-12 hr.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].C(OCC)(=O)C>C(O)C.CCCCCC>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)CCc1ccc(C(F)(F)F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)CCc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
1N NaOH solution was added to a stirred solution of ethyl 3-(3-chloro-4-(trifluoromethyl)phenyl)propanoate (I-85b: 4.8 g, 17.8 mmol) in ethanol and the resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (2% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure, quenched with ice, acidified with 1N HCl and extracted with DCM (2×150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the product 4.2 g (97.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.Br[N:13]1[C:17](=O)[CH2:16][CH2:15][C:14]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrCC1C=C2C(=CC=1)N=CC=N2>C(N)CCC.CCCCC.ClC1C=CC=CC=1>[CH2:14]([NH:13][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2)[CH2:15][CH2:16][CH3:17]
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: BrCc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCN
Solvent: CCCCC
Solvent: Clc1ccccc1
Product: CCCCNCc1ccc2nccnc2c1
Temperature: 85 °C

Procedure:
In a 50 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolved together with N-bromosuccinimide (2.32 g, 13.0 mmol) and benzoyl-peroxide (0.15 g, 0.62 mmol) in 31. g of chlorobenzene. The solution was stirred with heating at 85° C. for 2.0 hours to yield a reddish solution. The solution was cooled down to room temperature and one volume of pentane was added to facilitate the removal of succinimides. The precipitate was washed with pentane and the extracts were combined with the chlorobenzene solution. The yellow solution was vacuum dried to give a yellow residue mainly composed of 6-bromomethyl-quinoxaline. The yellow solid was dissolved in 19.0 g of n-butylamine to give a yellow solution that was stirred at room temperature for ˜5 minutes. Analysis of a sample showed that the 6-bromomethyl-quinoxaline was consumed to give exclusively 6-n-butylaminomethyl-quinoxaline as a deep yellow oil (1.71 g, 92% over all yield). MS (70 ev): 215 M+, 172 (M+—CH3—CH2—CH2),143 (M+—CH3—CH2—CH2—CH2).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:12][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(C)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COc1cc(CBr)ccc1C#N
Yield: 35.3 %

Procedure:
4.6 g (31.3 mmol) of 4-methyl-2-methoxybenzonitrile were brominated with 34.7 mmol of N-bromosuccinimide in the presence of catalytic amounts of azobisisobutyronitrile in 60 ml of 1,2-dichloroethane under reflux. 2.5 g of the product were obtained. 1H-NMR (DMSO-d6, δ in ppm): 7.75 (d, 1H), 7.35 (s, broad, 1H), 7.15 (d, broad, 1H), 4.73 (s, 2H), 3.95 (s, 3H)
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=O)[CH:2]=1.C1CCN2C(=NCCC2)CC1.[NH2:24][C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)C=1C1N=CC=CN=1.[CH3:43][O:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53][C:54](O)=[O:55]>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[C:10]([C:9]3[CH:1]=[CH:2][N:3]=[CH:6][N:8]=3)=[C:25]([NH:24][C:54](=[O:55])[CH2:53][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[O:46][CH2:45][O:44][CH3:43])[O:29][N:28]=2)=[CH:35][CH:34]=1
Reactant: Nc1onc(-c2ccc(F)cc2)c1-c1ncccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCOc1ccccc1CC(=O)O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COCOc1ccccc1CC(=O)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
In 16 mL of THF, 047 g of (2-methoxymethoxyphenyl)acetic acid and 0.5 g of CDI were dissolved and stirred at room temperature for 2 hours. Then 16 mL of a THF solution containing 0.92 g of DBU and 0.31 g of 5-amino-3-(4-fluorophenyl)-4-pyrimidinyl isoxazole was added, followed by 21 hours' stirring at room temperature. From the reaction solution the solvent was distilled off under reduced pressure. To the residue water was added and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and removed of the solvent by distillation under reduced pressure. The residue was purified on 50 g silica gel chromatography (eluent, chloroform:methanol=100:1) and the residue was washed with ether-hexane to provide 0.32 g yield: 60%) of the title compound.