Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([Cl:20])=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 100 %

Procedure:
1-benzoyl-3-piperidine carboxylic acid (1.01 g; 4.33 mmol) was suspended in dry dichloromethane (30 ml) under a nitrogen atmosphere. Thionyl chloride (3 ml; 41.3 mmol) was added and this mixture was heated to reflux for approximately 1 hour. It was then cooled to ambient temperature and evaporated under reduced pressure, giving 1-benzoyl-3-piperidinecarbonyl chloride (1.09 g) as a yellow oil. MS m/z (positive ion; run in CH3CN) 503 (dimer+; 30), 254 ([M+2]H+; 35), 252 (MH+; 100), 248 (50), 234 (60), 216 (25), 102 (30).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O[C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13](=[O:15])[O:14][C:21]3[C:18]([CH:19]=2)=[CH:17][CH:24]=[C:23]([OH:25])[CH:22]=3)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CCCCOc1ccc(CC(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(-c2cc3ccc(O)cc3oc2=O)cc1
Temperature: 0 °C

Procedure:
89.5 g (0.43 mol) of 4-butoxyphenylacetic acid (prepared by the method of McElvain, Carney; J. Am. Chem. Soc. 1946 (68), 2592-2599) and 30.0 g (0.22 mol) of 2,4-dihydroxybenzaldehyde are heated at 120° C. for 5 h in 100 ml of acetic anhydride and 120 ml of triethylamine. The still-hot solution is subsequently added to 3 l of ice-water, and the precipitated product is filtered off with suction and suspended in 1 l of water and 1.4 l of ethanol. After dropwise addition of 190 ml of conc. sulfuric acid, the batch is heated under reflux for 4 h and added to 3 l of water, and the precipitated product is filtered off with suction. The crude product is filtered through silica gel with hot toluene/ethyl acetate (1:1), the solvent is evaporated in vacuo, and the residue is recrystallised from toluene, giving 3-(4-butoxyphenyl)-7-hydroxychromen-2-one as colourless crystals.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][O:6][C:5](=[O:9])[N:4]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=O.[Na].[F:23][C:24]([F:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25](=[O:33])[CH2:26]P(=O)(OC)OC>C1COCC1.[Cl-].[Zn+2].[Cl-]>[F:23][C:24]([F:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25](=[O:33])/[CH:26]=[CH:1]/[C@H:3]1[CH2:8][CH2:7][O:6][C:5](=[O:9])[N:4]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)C(F)(F)c1ccccc1)OC
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1/C=C/C(=O)C(F)(F)c1ccccc1
Temperature: 60 °C

Procedure:
Horner-Emmons-Smith reaction: to a solution of isopropyl 7-[(4R)-4-formyl-2-oxo-1,3-oxazinan-3-yl]heptanoate (207 mg, 0.691 mmol) in THF (3 mL) was added Zinc chloride (0.5M in THF, 1.52 mL, 0.76 mmol, 1.1 eq) followed by the sodium salt of dimethyl (3,3-difluoro-2-oxo-3-phenylpropyl)phosphonate (270 mg, 0.898 mmol, 1.3 eq) as a solid and the mixture was heated to 60° C. o/n and concentrated. The residue was purified by column chromatography (80% ethyl acetate/hexanes) to give the desired product isopropyl 7-{(4R)-4-[(1E)-4,4-difluoro-3-oxo-4-phenylbut-1-en-1-yl]-2-oxo-1,3-oxazinan-3-yl}heptanoate as a light yellow oil. MS (+ESI): m/z 452 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:16]=[C:15](Cl)[S:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19]>>[NH2:11][C:12]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:9])[F:1])=[CH:4][CH:5]=2)[S:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: FC(F)(F)c1ccccc1
Product: Nc1cc(-c2ccc(C(F)(F)F)cc2)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from 4-trifluoromethylbenzene boronic acide and 3b by following the procedure in example 3c. This compound is a white solid: MS (ES) 323 (M+H)+; 1H NMR (400 MHz, CD3OD)δ7.80 (d, 2 H, J=8.2 Hz), 7.72 (d, 2 H, J=8.2 Hz), 7.02 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I>CN(C=O)C.O>[Cl:17][CH2:18][CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (5 g, 26.0 mmol) in DMF (100 ml), cooled to 0° C. was added sodium hydride (3.12 g, 78 mmol). The mixture was stirred until bubbling had ceased, then 1-chloro-3-iodopropane (8.23 ml, 78 mmol) was added. The reaction was kept in an ice bath and allowed to warm to room temperature slowly, then stirred overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organics were then washed with a 1:1 mixture of brine and water (3×), then brine (1×). The organic phase was dried, filtered and concentrated then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.22 g, 19.43 mmol, 74.7% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH3:19]>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([NH2:19])=[O:18])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: N
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(N)=O)o2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-furan-2-carboxylic acid and ammonia to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:3]=1
Reactant: Cc1cccc(-c2nc(C)cc(Cl)n2)c1
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2cc(C)nc(-c3cccc(C)c3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine (100 mg, 0.457 mmol) and m-anisidine (51 μl, 0.457 mmol) similar to Example 11 as a pale yellow solid (11 mg, 8%). 1H NMR (DMSO-d6): 8.09 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.54-7.49 (m, 4H), 7.35 (t, J=8.1 Hz, 1H), 7.21 (s, 1H), 6.78 (s, 2H), 3.81 (s, 3H), 2.43 (s, 6H).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].CC(C)(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C.P(=O)(O)(O)O.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:4][C:2]([NH:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: C=C(C)C
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)Nc1cccnc1N1CCNCC1
Reaction time: 1 h

Procedure:
Isobutylene (10 ml) is condensed into a solution of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 200 mg) in methylene chloride (10 ml) at -70°. Phosphoric acid (85%, 50 μl) is added and the mixture stirred for 60 minutes. Boron trifluoride etherate (200 μl) is added dropwise and the resulting suspension is stirred 8 hours at reflux and overnight at 20°-25° allowing the isobutylene to evaporate. The suspension is diluted with water and ammonium hydroxide is added until basic to pH paper and then extracted with methylene chloride (3 ×). The combined extracts are dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure to a liquid which is flash chromatographed (silica gel, 230-400 mesh), eluting with methanol/chloroform (3/20). The appropriate fractions are pooled and concentrated to give an oil. The NMR, CMR, IR, and MS (m/e) M+234 support the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])[CH3:35]
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 70 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.43–7.39 (m, 2H), 7.30–7.27 (m, 2H), 7.04–7.00 (m, 2H), 6.96 (d, 1H, J=7.2 Hz), 6.77 (br s, 1H), 3.30 (dd, 2H, J=5.6, 11.6 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.49 (m, 1H), 2.34 (t, 4H, J=6.4 Hz), 2.19 (s, 3H), 1.99–1.80 (m, 6H), 1.73–1.60 (m, 10H); ESMS m/e: 480.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N+](C1C=CC(O[C:36](=[O:44])[O:37][CH2:38][C:39]2[CH:43]=[CH:42][O:41][CH:40]=2)=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[O:41]1[CH:42]=[CH:43][C:39]([CH2:38][O:37][C:36](=[O:44])[N:2]([CH3:1])[CH:3]2[CH2:16][C:15]3[C:6]([CH3:25])([CH:7]4[CH:12]([CH2:13][CH:14]=3)[CH:11]3[CH2:17][CH2:18][CH:19]5[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]35[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)=[CH:40]1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: O=C(OCc1ccoc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCc6ccoc6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
Compound 7B (10 mg, 0.029 mmol), carbonic acid furan-3-ylmethyl ester 4-nitro-phenyl ester (2.4 mg, 0.032 mmol) and triethylamine (12.0 μL, 0.087 mmol) were dissolved in THF (1 mL) and stirred at room temperature overnight. The crude reaction mixture was purified on silica gel column using 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (10.1 mg, 74.2% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl.Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of commercially-available 4-bromomethyl benzenesulfonyl chloride (1.0 g, 3.71 mmol) in dichloromethane (8 ml) at 0° C. under an argon atmosphere, is added triethylamine (0.575 ml, 4.1 mmol), in one portion, followed by morpholine (0.359 ml, 4.1 mmol). The reaction mixture is stirred for 20 h, warming up slowly to room temperature. The reaction mixture is then diluted with 2N HCl aq (40 ml) and extracted in dichloromethane (20 ml), dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound. No mass ion detected.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/c1cc2cccc(Cl)c2nc1Cl
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a solution of 2,8-dichloroquinoline-3-carboxaldehyde (43.0 g, 0.19 mol) in anhydrous THF (500 mL) was added titanium(IV) isopropoxide (114 mL, 0.38 mol) at r.t. After stirring for 15 minutes, (R)-2-methyl-2-propanesulfinamide (23.0 g, 0.19 mol) was added and stirring was continued for 17 h at r.t. Water (1 L) was added to the reaction mixture and the resulting precipitate was filtered and washed with DCM. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (61 g, 97%) as a pale yellow solid. δH (CDCl3) 9.11 (1H, s), 8.83 (1H, s), 7.93 (1H, dd, J 7.54, 1.31 Hz), 7.88 (1H, dd, J 8.22, 1.31 Hz), 7.55 (1H, t, J 7.88 Hz), 1.33 (9H, s).
Reaction SMILES: Br[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=3[O:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)=O.CC(C)=O.[NH2:31][C:32]([NH2:34])=[S:33]>>[Br:18][C:15]1[CH:16]=[CH:17][C:9]2[C:8]3[S:19][C:5]([C:3]4[N:31]=[C:32]([NH2:34])[S:33][C:2]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:6][C:7]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:14]=1
Reactant: NC(N)=S
Reactant: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)C(Br)c1ccccc1Cl
Solvent: CC(C)=O
Product: Nc1nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(-c2ccccc2Cl)s1
Temperature: 80 °C
Yield: 84.6 %

Procedure:
2-Bromo-1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone (ca. 2.3 mmol) was suspended in acetone (15 mL, 0.20 mol) and treated with thiourea (0.26 g, 0.0034 mol;). The mixture was sealed and heated at 80° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated, suspended in water and the solid was collected by filtration. The solid was rinsed with water to give 953 mg of 271 as a light yellow solid. 1H NMR (dmso-d6, 500 MHz) δ 7.64 (m, 1H), 7.53 (m, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.17 (m, 1H), 6.47 (s, 1H), 4.19 (t, 2H), 2.95 (t, 2H). MS (ESI) 491.0
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.C(=O)([O-])[O-].[Na+].[Na+].[C:27]1(C)C=CC=C[CH:28]=1>C(O)C.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([O:19][CH2:27][CH3:28])=[O:18])[CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1ccccc1
Reactant: CN1c2ccccc2Sc2ccc(CC(=O)O)cc21
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc2c(c1)N(C)c1ccccc1S2

Procedure:
18.0 g of (10-methyl-10H-phenothiazin-2-yl)acetic acid are dissolved in a mixture of 400 ml of toluene and 200 ml of ethanol, and 5 ml of concentrated sulfuric acid are added. In a water separator filled with molecular sieve, the reaction mixture is heated at the boil under reflux for twelve hours. The reaction mixture is then cooled in an ice bath, and 200 ml of water are added. The mixture is then neutralized by addition of solid sodium carbonate. The product is then extracted five times with in each case 250 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane=>n-heptane:ethyl acetate=10:1. This gives 17.0 g of ethyl (10-methyl-10H-phenothiazin-2-yl)acetate as a yellow oil. C17H17NO2S (299.39), LCMS (ESI): 300.1 (M+H+), Rf (n-heptane:ethyl acetate=3:1)=0.34.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:18]([O-])=O>CO.C1CCCCC=1.[Pd]>[N+:15]([C:14]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]=[C:6]2[C:5]=1[NH:4][CH2:3][CH2:2][NH:18]2)([O-:17])=[O:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NCCCl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCCC1
Product: COC(=O)c1cc2c(c([N+](=O)[O-])c1)NCCN2
Temperature: 25 °C
Yield: 32.9 %

Procedure:
To a solution of crude methyl 4-[(2-chloroethyl)amino]-3,5-dinitrobenzoate (D208) (9 g, 19.2 mmol, 1 equiv) in MeOH (75 ml) and cyclohexene (150 ml) was added 10% palladium on charcoal (50% wet, 4.5 g, 25% w/w) and the resulting mixture was refluxed for 3 h then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the solvent was removed in vacuo. The residue was partitioned between AcOEt and a 2N aqueous HCl solution and the two layers were separated. The aqueous phase was extracted twice with AcOEt and the combined organic layers were washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 1/1) gave methyl 8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D209) (1.5 g, 34%) as a red solid. [M−H]−=236.2, RT=2.65 min.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[F:30][C:31]1[C:36]([F:37])=[C:35]([C:38]#[N:39])[CH:34]=[CH:33][C:32]=1O.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[C:36]([F:37])[C:31]=2[F:30])=[O:26])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(C(=O)Oc2ccc(C#N)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.11 mol of dicyclohexylcarbodiimide and 20 ml of toluene is added to a mixture of 0.1 mol of p-pentylbenzoic acid, 0.1 mol of 2,3-difluoro-4-cyanophenol (prepared according to Example 4), 1.5 g of 4-N,N-dimethylaminopyridine and 200 ml of toluene. After the mixture has been stirred at room temperature for 4 hours, 0.4 g of oxalic acid is added and stirring is continued for a further 30 minutes. Customary working up gives 4-(4-pentylbenzoyloxy)-2,3-difluorobenzonitrile, mp. 33° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:22](I)[CH3:23]>CN(C=O)C>[NH2:12][C:11]1[C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][CH2:22][CH3:23]
Reactant: CCI
Reactant: COC(=O)c1cc(N)c(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1cc(C(=O)OC)cc([N+](=O)[O-])c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of methyl 3,4-diamino-5-nitrobenzoate (D204) (1.5 g, 7.1 mmol, 1 equiv) in DMF (30 ml) at room temperature was added K2CO3 (2.2 g, 16.0 mmol, 2.25 equiv) then ethyl iodide (1.28 ml, 16.0 mmol, 2.25 equiv). The resulting suspension was stirred at 60° C. for 2 h then ethyl iodide (1 ml, 12.5 mmol, 1.8 equiv) was added and the resulting mixture stirred for another 6 h then cooled to room temperature and partitioned between AcOEt and a saturated aqueous NaHCO3 solution. The two layers were separated and the organic phase washed with H2O, dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O to give methyl 4-amino-3-(ethylamino)-5-nitrobenzoate (D205) (0.85 g, 50%) as a red solid which was used in the next step without further purification. [M+H]+=240.2, RT=2.95 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Cl:37][CH2:38][C:39](Cl)=[O:40]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]([C:39](=[O:40])[CH2:38][Cl:37])[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCl)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1 g (2.3 mmol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [compound (A)] is dissolved in 170 ml of abs. DMF under argon. 110 mg (4.6 mmol) of sodium hydride are added, and the mixture is stirred at RT for 20 min. Then 3.5 g (31 mmol) of chloroacetyl chloride are added, keeping the reaction temperature at RT. After 30 min, 25 ml of water are added while cooling, and the mixture is left to stand at RT for two days. The solvent is then removed in vacuo, during which the temperature should not rise above +25° C. The residue is taken up in 500 ml of dichloromethane and extracted five times with 200 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to a volume of about 50 ml. While stirring, 200 ml of diethyl ether are added, and the precipitate (mostly unreacted starting material) is then filtered off. The mother liquor is concentrated and the residue is purified by flash chromatography on silica gel with toluene/ethanol 10:1 as eluent. The appropriate fractions are combined, and the solvent is removed. The residue is lyophilized from dioxane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)O)c2)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)NC(C)C)c2)=C(C)C1=O
Yield: 16.3 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (65 mg, 0.19 mmol) obtained in Example 31 and isopropylamine (0.019 ml, 0.21 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (12 mg, 0.031 mmol, yield 16%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH2:8][C:9]5[O:4][CH:3]=[CH:43][CH:44]=5)[CH3:11])[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5ccco5)c4)cc23)CC1
Yield: 29 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(2-furanyl)-N-methylmethanamine (111 mg, 1.0 mmol) for N-methylethanamine to afford 19.0 mg of the title compound (29.0%).