Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29][CH2:28]2.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][C:36]([N:7]1[CH2:6][CH2:5][N:4]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][N:19]=4)(=[O:16])=[O:15])=[CH:12][CH:13]=3)[CH2:3][C@@H:2]1[CH3:1])=[O:37])[CH2:30][CH2:29][CH2:28]2
Reactant: C[C@H]1CN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CCN1
Reactant: O=C(O)CN1CCCc2cc(Cl)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CCN1C(=O)CN1CCCc2cc(Cl)ccc21

Procedure:
Synthesized according to general procedure 9, method A. The reaction was set up with 0.1 mmol (S)-4-(3-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide, 0.15 mmol 2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)acetic acid, 0.15 mmol BOP reagent, 0.15 mmol triethylamine and DMF (300 μL). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=541.5; tR=2.96 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][N:3]=1.[OH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>[Pd].COCCOC>[OH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2-c2ccccc2)C1
Reactant: OB(O)c1ccccc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)ncc2-c2ccccc2)C1
Yield: 88.4 %

Procedure:
A mixture of (S)-tert-butyl 3-(2-chloro-5-phenylpyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.153 g, 0.408 mmol), 2-hydroxyphenylboronic acid (0.169 g, 1.24 mmol), palladium catalyst (0.013 g, 0.020 mmol) and 1 M aqueous Na2CO3 (0.82 mL, 0.82 mmol) in DME (4 mL) was refluxed for 24 hours. After cooling, water (50 mL) was added and the aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to give the title compound as an oil (0.156 g, 89%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:6]=[C:7]([O:12]C)[C:8]=1[CH2:9][CH2:10][CH3:11].Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:6]=[C:7]([OH:12])[C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: CCCc1c(OC)cc(C=Cc2cccc(C(=O)O)c2)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1c(O)cc(C=Cc2cccc(C(=O)O)c2)cc1O
Yield: 86 %

Procedure:
This material was prepared from 3-[2-(3,5-dimethoxy-4-1-propylphenyl)ethenyl]benzoic acid 2B and pyridine hydrochloride in 86% yield in the same way as described in Example 3. 1HNMR (DMSO-d6, ppm): δ 1.22 (d, J=7.0 Hz, 6H), 6.48 (s, 2H), 7.03 (d, J=17 Hz, 1H), 7.12 (d, J=17 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.7-7.9 (m, 2H), 8.06 (s, 1H), 9.12 (s, 2H).
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7](O)=[O:8])[C:4](=[O:19])[CH:3]=[CH:2]1.C(Cl)[Cl:22]>>[C:1]1(=[O:20])[N:5]([CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([Cl:22])=[O:8])[C:4](=[O:19])[CH:3]=[CH:2]1
Reactant: ClCCl
Reactant: CCCCCCCCCC(C(=O)O)N1C(=O)C=CC1=O
Product: CCCCCCCCCC(C(=O)Cl)N1C(=O)C=CC1=O
Temperature: 72.5 °C

Procedure:
24.0 g (0.085 mole) maleimidoundecanoic acid were dissolved in 50 ml of dry CH2Cl2 in a 250 ml round bottomed flask fitted with a stirrer, reflux condenser and CaCl2 drying tube, and were treated with 31.0 g (0.24 mole) oxalyl and boiled under reflux for 15 hours at an oil bath temperature of 70 to 75° C. Subsequently, the CH2Cl2 was first distilled off under normal pressure, and the oxalyl chloride was distilled off at 0.01 mbar. On account of its susceptibility to hydrolysis, the dark-coloured residue was not purified further, but was immediately used for further syntheses. Yield: 2.5 g=100% theoretical. The maleimidoundecanoic acid chloride had a purity of 94% as determined by GC/MS.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[OH:18][CH:19]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[N:32]=[CH:31]2)[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>ClCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:43][CH:41]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:38]([CH3:40])[CH3:39])[N:33]1[C:34]2[C:30](=[CH:29][C:28]([C:19]([C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[C:22]#[N:23])=[O:18])=[CH:36][CH:35]=2)[CH:31]=[N:32]1)[CH3:42]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(C(O)c3ccccc3C#N)ccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(C(=O)c3ccccc3C#N)ccc21
Temperature: 25 °C
Yield: 41.3 %

Procedure:
A solution of dimethylsulfoxide (71 μL, 1.0 mmol) in dichloromethane (1.5 mL) was cooled to −60° C. Addition of oxalyl chloride (44 μL, 0.50 mmol) was followed by addition of triethylamine (0.29 mL, 2.1 mmol) and 2-(hydroxy{1-[tris(1-methylethyl)silyl]-1H-indazol-5-yl}methyl)benzonitrile (0.17 g, 0.42 mmol in 2.0 mL of dichloromethane). The solution was allowed to warm to room temperature then diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted (2×100 mL ethyl acetate). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 5:1 hexanes/ethyl acetate) gave 0.070 g (42%) of 2-({1-[tris(1-methylethyl)silyl]-1H-indazol-5-yl}carbonyl)benzonitrile. 1H NMR (400 MHz, CDCl3): 8.32 (d, 1H), 8.13 (m, 1H), 8.01 (dd, 1H), 7.87 (m, 1H), 7.68 (m, 5H), 1.81 (m, 3H), 1.13 (d, 18H); MS (EI) for C24H29N3OSi: 248 (M−Si(iPr)3).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1.P(CCCC)(CCCC)CCCC>C1COCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:30]3[CH:31]=[CH:32][C:27]([CH2:26][C:25]([O:24][CH3:23])=[O:34])=[CH:28][CH:29]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(CC(=O)OC)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 63.8 %

Procedure:
To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (349 mg, 1.13 mmol) in dry THF (22.5 mL) at 0° C. (ice/water bath) under nitrogen was added methyl-4-hydroxyphenylacetate (187 mg, 1.13 mmol) followed after 1 minute by ADDM (578 mg, 2.25 mmol) in one portion. The resulting orange cloudy mixture was stirred for 3 minutes and then treated with nBu3P (562 μL, 2.26 mmol) drop-wise over 1 minute. The resulting pale yellow/orange mixture was then allowed to warm slowly to rt over 64 hours. The cloudy mixture was then reduced under vacuum and the residue partitioned between EtOAc (50 mL) and water (50 mL) and the layers separated. The aqueous was then re-extracted with EtOAc (50 mL) and the combined organic layer washed with brine (100 mL) dried (MgSO4), filtered and reduced to give an oil which was purified by SPE (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 5:1) to give the title compound (330 mg).
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.O.[OH:25][N:26]1C2C=CC=CC=2N=N1.Cl.NO.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([CH:7]=[CH:8][C:9]([NH:26][OH:25])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C=CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(C=CC1CCCCC1)NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
to a solution of 3-Cyclohexylacrylic acid (5.30 g, 31.3 mmol) in DMF (100 mL) was added EDC (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (7.80 g, 40.7 mmol) and HOBt (1-hydroxybenzotriazole hydrate) (5.07 g, 37.6 mmol). After stirring for 30 min at room temperature hydroxylamine hydrochloride (3.26 g, 47.0 mmol) and triethylamine (6.94 mL, 50.1 mmol) were added. After additional 18 hours stirring at room temperature the precipitate was filtered and washed with DMF. The DMF phases were combined. The solvent was concentrated in vacuo. 1 N HCl (50 mL) was added. After extraction with ethyl acetate (3×100 mL) and dichloromethane (2×100 mL) the organic layers were combined, washed with 1 N HCl (10 mL) and sodium chloride saturated solution (10 mL) and dried with magnesium sulfate. The solvent was removed in vacuo. The product was crystallized from ethyl acetate by addition of petroleum ether. This step removed large amounts of HOBt, the substance was then further purified by preparative HPLC using an acetonitrile/water gradient. This yielded (1.54 g, 9.08 mmol) of 3-Cyclohexyl-N-hydroxy-acrylamide. 1H NMR (300 MHz, [D6-DMSO]: δ=0.99-1.35 (m, 5H) and 1.56-1.73 (m, 5H) (cyclohexyl-CH2), 2.00-2.13 (m, 1H, cyclohexyl CH), 5.67 (d, J=15.7 Hz, 1H, C═C—H), 6.58 (dd, J=15.7 and J=6.3 Hz, 1H, C═C—H), 8.77 (s, 1H) and 10.49 (s, 1H) (NH and OH). 13C NMR (75 MHz, [D6-DMSO]: δ=25.2, 25.5, 31.5 (cyclohexyl-CH2), 41.1Acyclohexyl-CH), 118.8 and 147.1 (C═C), 162.8 (C(═O)NHOH). MS: m/z calcd for (C9H15NO2) [M+H]+ 170; found 170.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=O.[CH3:19][CH:20]([CH3:44])[CH2:21][NH:22][C@H:23]1[CH2:28][C@@H:27]([C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH2:26][N:25]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:24]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:22]([CH2:21][CH:20]([CH3:44])[CH3:19])[C@H:23]1[CH2:28][C@@H:27]([C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH2:26][N:25]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:24]1)=[O:18]
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCn1c(C(=O)O)cc2ccccc21
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (210 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (270 mg) and N,N-diisopropylethylamine (560 μl) were dissolved in 1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (360 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-10:0) was concentrated under reduced pressure to give the object product (83 mg).
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])([O:3][CH3:4])=[O:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1>C(#N)C.CCOCC>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:11])=[O:12])=[O:15])[N:19]=1
Reactant: COC(=O)C1=C(S(=O)(=O)N=C=O)CCC1
Reactant: COc1cc(C)nc(N)n1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1=C(S(=O)(=O)NC(=O)Nc2nc(C)cc(OC)n2)CCC1

Procedure:
The sulfonyl isocyanate product (5 g) of Example 3 was diluted to a concentration of 1.5M with dry acetonitrile and 2.0 ml of this solution was added to a stirred suspension of 0.31 g 4-methoxy-6-methylpyrimidine-2-amine in 4.0 ml of dry acetonitrile under a nitrogen atmosphere at room temperature. After stirring several hours, the mixture was diluted with ether to precipitate the product which was collected by filtration and dried; m.p. 161°-163°. An infrared spectrum (nujol) exhibited absorptions at 1730 and 1700 cm-1, and an NMR (90 MHz) in CDCl3 solution exhibited absorptions at 2.1 (CH2), 2.45 (CH3), 3.0 (CH2 ×2), 3.75 (CH3O), 3.95 (CH3O), 6.3 (CH), 7.9 (NH), 13.8 (NH), ppm indicating the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>>[CH2:17]([O:16][C:12]([CH2:13][CH2:14][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCCNC1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCN1CCCC(C(=O)OCC)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
Ethyl 3-piperidinecarboxylate (3.14 g, 20 mmol) was dissolved in ethyl acrylate (2.50 g, 25 mmol) and stirred at 80° C. (12 h), and then the reaction was concentrated in vacuo, and purified by PTLC (EtOAc/hexanes=3/1) to give 15a (4.64 g, 90%) as a pale yellow oil: Rf 0.51 (EtOAc/hexanes=3/1); IR (neat) 2944, 2806, 1735, 1455, 1376, 1309 cm−1; 1H NMR (CDCl3) δ 1.17-1.22 (m, 6H), 1.35-1.51 (m, 2H), 1.62-1.68 (m, 1H), 1.83-1.89 (m, 1H), 1.95-2.02 (m, 1H), 2.11-2.18 (m, 1H), 2.40-2.50 (m, 3H), 2.62-2.70 (m, 3H), 2.91 (dd, J=1.8, 8.1 Hz, 1H), 4.03-4.12 (m, 4H); 13C NMR (CDCl3) 14.3 (2C), 24.7, 26.9, 32.5, 41.9, 53.5, 53.9, 55.3, 60.3, 60.4, 172.6, 174.1 ppm; MS (+CI) 258 [M+1]+; Mr (+CI) 258.170 30 [M+1]+ (calcd for C13H24NO4 258.170 53).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:8]=1[CH:9]=[O:10].[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.CC1C=C(C=[C:34]([CH3:37])[C:35]=1O)C=O>>[CH3:15][C:14]1[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:22]([CH2:35][CH2:34][CH3:37])[CH2:21][CH2:20][CH3:26])=[C:8](/[CH:9]=[CH:17]/[C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:11]=[C:12]([CH3:16])[CH:13]=1.[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: Cc1nc2ccccc2s1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cc1cc(C)c(OCCCCCl)c(C=O)c1
Product: CCCN(CCC)CCCCOc1c(C)cc(C)cc1/C=C/c1nc2ccccc2s1

Procedure:
The title compound was prepared according to the procedure of Example 5 above using 4-chlorobutoxy-3, 5-dimethylbenzaldehyde in place of 4-chlorobutoxybenzaldehyde and using 2-methylbenzothiazole in place of 2-methylbenzoxazole. 4-Chlorobutoxy-3, 5-dimethylbenzaldehyde was prepared from 3,5-dimethyl-4-hydroxybenzaldehyde according to the procedure Example 1 above.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C(O)(=O)C>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2cnccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2CNCCC21
Yield: 74.6 %

Procedure:
A mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.45 g, 11.23 mmol) and palladium hydroxide on carbon (20%, 1 g, 1.424 mmol) in ethanol (8 ml)/acetic acid (16 mL) was hydrogenated at 50 psi and 60° C. overnight. The reaction mixture was filtered through celite. Solvent was evaporated in vacuo and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, The crude was be used without purification. tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1.896 g) was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[C:16]([OH:23])=[C:15]([CH3:24])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([S:13][CH3:14])=[S:12])[CH2:7][CH2:6]1.Cl.CO>O>[CH3:22][O:21][C:17]1[C:16](=[O:23])[C:15]([CH3:24])=[C:3]([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([C:11]([S:13][CH3:14])=[S:12])[CH2:9][CH2:10]2)[C:2](=[O:1])[C:18]=1[O:19][CH3:20]
Reactant: COc1c(O)c(C)c(CN2CCN(C(=S)SC)CC2)c(O)c1OC
Agent: Cl
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(CN2CCN(C(=S)SC)CC2)=C(C)C1=O
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To 700 mg (1.88 mmol.) of methyl 4-(2,5-dihydroxy-3,4-dimethoxy-6-methylbenzyl)-1-piperazinecarbodithioate were added 7 ml of 1-N hydrochloric acid and 17 ml of methanol. The mixture was chilled with ice, and to the mixture was dropwise added a solution of 1.76 g (7.52 mmol.) of FeCl3.6H2O in 5 ml of water. The resulting homogeneous red-colored solution was stirred for 30 min. and placed under reduced pressure at a temperature of lower than 50° C. to distill off methanol. To the residue was added 50 ml of ethyl acetate, and further added portionwise a saturated aqueous sodium hydrogen carbonate solution to adjust the solution to pH 10. A precipitated brownish red solid was removed by filtration. Thus obtained organic filtrate was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was crystallized from ethanol, and collected by filtration, to give 540 mg of the desired compound as an orange-brown crystalline powder, m.p. 115°-116° C., yield 77.6%.
Reaction SMILES: F[C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].O.[NH3:28]>CN(C)C=O.CO>[NH2:28][C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]
Reactant: N
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(N)c([N+](=O)[O-])c2c1=O
Yield: 71 %

Procedure:
Ethyl 6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate (10.04 g, 27.12 mmol) was dissolved in dimethylformamide (150 ml), and 28% ammonia water (32.1 ml) was added dropwise thereto while stirring and cooling with ice. While sealing the reaction solution in a sealed tube, it was stirred at room temperature for 4 hours. The reaction solution was then dissolved in methanol (200 ml) and concentrated under a reduced pressure. The residue obtained was purified by recrystallization from a mixed solvent of 2-propanol/chloroform/28% ammonia water, and after drying under a reduced pressure, 7.07 g (71%) of the title compound was obtained as a yellow powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:14]2)[CH3:10].C(OC(C)C)(=O)C>Cl>[C:1]([C:19]1[CH:18]=[C:17]2[C:13](=[CH:12][C:11]=1[CH2:9][CH3:10])[CH2:14][CH:15]([NH:20][C:21](=[O:26])[C:22]([F:24])([F:23])[F:25])[CH2:16]2)(=[O:3])[CH3:2]
Reactant: CCc1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)OC(C)C
Product: CCc1cc2c(cc1C(C)=O)CC(NC(=O)C(F)(F)F)C2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
A 250 mL, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with acetyl chloride (37.68 g, 480 mmol) and cooled to 0±5° C. Aluminum chloride (13.33 g, 100 mmol) was added in 4×3.33 g portions at 0±5° C. while maintaining the temperature below 15° C. The resulting solution was cooled to 0±5° C. and stirred for 5 minutes. N-(5-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (10.29 g, 40 mmol) was added in 5×2.06 g portions over 40 minutes at 10-minute intervals, while maintaining the temperature 0-10° C. The tan solution was stirred at 0±5° C. for an additional 30 minutes. The solution was added to a pre-cooled (0-5° C.) mixture of 1 N HCl (120 mL) and isopropyl acetate (13 mL) in a 500 mL, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the temperature at 0-25° C. over a period of 20 minutes. The 250 mL, round-bottomed flask was rinsed with 3 mL of acetyl chloride followed by 13 mL of heptane and added to the batch. The resulting slurry was warmed to 40-45° C. over a period of 30 minutes and then stirred for additional 1 hour. Heptane (39 mL) was added and the slurry was stirred at 40-45° C. for an additional 15 minutes. The slurry was cooled to 20-25° C. and stirred for 1 hour. The solids were collected by filtration using a Büchner funnel with suction over polypropylene filter paper. The filter cake was washed with 2×10 mL heptane/isopropyl acetate (80:20 v/v), followed by 1 N HCl (36 mL) and deionized water (2×25 mL). The solids were dried at 60-65° C. under vacuum (13-40 mbar, 10-30 torr) with nitrogen bleeding to obtain 11.3 g (94% yield) of N-(5-acetyl-6-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (m.p. 124-127° C.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]1([S:15]([O:18][C:19]2[CH:27]=[CH:26][C:22]3[S:23][CH:24]=[CH:25][C:21]=3[CH:20]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:5]([C:25]1[C:21]2[CH:20]=[C:19]([O:18][S:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:16])=[O:17])[CH:27]=[CH:26][C:22]=2[S:23][CH:24]=1)(=[O:7])[CH3:6]
Reactant: O=S(=O)(Oc1ccc2sccc2c1)c1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
Powdered aluminum chloride (1.34 g, 10 mmol) was suspended in dichloromethane (10 ml). To the suspension was added dropwise acetyl chloride (1.02 ml, 14.3 mmol) over 5 minutes with stirring and under ice-cooling. Subsequently, a solution of the compound (8) (2.075 g, 7.2 mmol) prepared above in dichloromethane (6 ml) was added dropwise over 15 minutes. After being stirred for 2 hours at the same temperature and then for 2.5 hours at room temperature, the solution was poured into ice-water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethyl acetate (3 ml) and hexane (3 ml) to provide 2.01 g of the title compound (9). Yield: 84.4% mp 129-130° C.