Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13](=O)([O-])[O-].[Na+].[Na+].IC>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
4-Fluoro-2-methyl-5-nitro-phenol (1.08 g, 6.3 mmol) was dissolved in acetone (100 ml). To this was added solid sodium carbonate (2 eq, 1.34 g) and iodomethane (10 eq, 3.75 ml). The mixture was allowed to stir at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give 1-fluoro-4-methoxy-5-methyl-2-nitro-benzene (1.18 g, quantitative) as a pale yellow solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f47) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.N1C=CC=CC=1.Cl[C:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])=[O:20]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])=[O:20])[CH:3]=2)[NH:7]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Yield: 60.8 %

Procedure:
5-Amino-1,3-dihydro-indol-2-one 30c (500 mg, 3.38 mmol) was dissolved in 10 ml of dichloromethane under stirring at room temperature, and pyridine (470 μl, 5 mmol) was added to the solution at −40° C. in a dry ice-acetone bath. Acetic acid chlorocarbonylmethyl ester (473 mg, 3.48 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above reaction solution. Upon completion of the addition, the dry ice-acetone was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water (10 ml×3) and recrystallized to obtain the title compound acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-methyl ester 44a (510 mg, yield 60.7%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][CH:2]1[N:7]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of (±)-tert-butyl 3-methylpiperazine-1-carboxylate (1.5 g), 1-fluoro-4-nitrobenzene (1.06 g) and potassium carbonate (2.07 g) in dimethyl sulfoxide (15 ml) was stirred at 120° C. for 15 hours. The reaction mixture was cooled to room temperature and poured into water (30 ml). The mixture was extracted with ethyl acetate three times. The combined organic layers were washed successively with water (twice) and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 2:1) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1.O1CCOCC1.[OH-].[K+]>O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([OH:13])=[O:12])=[CH:19][CH:20]=1
Reactant: CCCC(CC(=O)OC)(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Methyl 3,3-bis(4-methoxyphenyl)hexanoate (5.2 g, 15.2 mmol) was introduced into 20 ml of dioxane, KOH (1.05 g, 18.2 mmol) was added, and the mixture was boiled for about 1 h. It was subsequently diluted with water and washed with ethyl acetate, and the aqueous phase was then adjusted to pH 3 with dilute HCl and extracted with ethyl acetate. The organic phase was then washed with saturated NaCl solution, dried over MgSO4 and concentrated. Chromatography on silica gel (CH2Cl2 /methanol 3%) resulted in 4.1 g of a pale yellowish oil (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[NH2:20])[C:15]#[N:16]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]1[NH:11][C:12]2[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[CH:18][C:19]=2[N:20]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CS(C)=O
Product: N#Cc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 20 ml scint. vial was added 0.500 g (2.86 mmol) of 2,6-Dichloro-benzaldehyde, 0.3804 g (2.86 mmol) of 3,4-diamino-benzonitrile, and 6 mL DMSO. To the brown solution was added 0.1995 g (1.23 mmol) of FeCl3. Allowed stir at r.t. open to air for 18 h. Extracted with EtOAc and washed with water, and brine. Dried and purified on silica gel column chromatography (EtOAc/Hep, 1:9 to 7:3) to give of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.72 (m, 4H) 7.79 (br. s., 1H) 8.27 (br. s., 1H) 13.48 (br. s., 1H). MS (m/z) 288.1 M (+1), tR=1.18, Meth 10
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[C:10](=O)[CH3:11])=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=1)([O-:3])=[O:2].[NH2:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1>C(O)(C)C>[C:13]([C:9]1[CH:8]([C:7]2[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:18]([F:19])([F:20])[F:21])[C:24]2[C:25](=[O:29])[NH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:10]=1[CH3:11])(=[O:15])[CH3:14]
Reactant: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1C(F)(F)F)C(C)=O
Reactant: Nc1cc[nH]c(=O)c1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
1.28 g (4.24 mmol) of 3-[4-nitro-2-(trifluoromethyl)benzylidene]pentane-2,4-dione and 484 mg (4.24 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] are dissolved in 25 ml of isopropanol and heated under reflux under argon for 12 h. Cooling is followed by filtration, and the remaining solid is washed with diethyl ether (40 ml). 990 mg (58% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
Methyl iodide (36 ml) was added to a mixture of methyl 3,5-dihydroxybenzoate (104 g), potassium carbonate (79 g) and dimethylformamide (1200 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between water (2.5 liter) and petrol (b.p. 60°-80° C., 600 ml). The aqueous layer was washed with petrol (b.p. 60°-80° C., 600 ml) and then extracted with toluene (2×1 liter). The toluene extracts were combined, washed with water (4×800 ml), dried (MgSO4) and evaporated to give methyl 3-hydroxy-5-methoxybenzoate as an oil (33 g, 30%).
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.[NH2:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[C:45](=[O:55])[C:46]([CH3:54])=[CH:47][N:48]2[CH3:53]>>[CH3:53][N:48]1[C:49]2[C:44](=[C:43]([NH:42][C:14]3[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])=[CH:27][C:26]=4[O:40][CH3:41])[N:15]=3)[CH:52]=[CH:51][CH:50]=2)[C:45](=[O:55])[C:46]([CH3:54])=[CH:47]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: Cc1cn(C)c2cccc(N)c2c1=O
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3c(=O)c(C)cn4C)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (99.5 mg, 0.219 mmol) and 5-amino-1,3-dimethylquinolin-4(1H)-one (Compound 299A, 49.2 mg, 0.261 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 14.66 (s, 1H), 8.88 (s, 1H), 8.60 (br s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.43-7.63 (m, 2H), 7.18 (d, J=8.6 Hz, 1H), 7.05 (s, 1H), 6.90 (d, J=7.8 Hz, 1H), 3.95-4.05 (m, 4H), 3.80 (s, 3H), 3.76 (s, 3H), 3.28 (d, J=21.5 Hz, 2H), 1.98 (s, 3H), 1.20 (t, J=6.9 Hz, 6H). MS (ES+): m/z 606.16 (60) [MH+]. HPLC: tR=1.46 min (TOF, polar—3 min).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C1C=C(Br)C=C(C(F)(F)F)C=1.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([CH3:43])[CH:41]=2)[N:36]=[C:35]([CH3:44])[CH:34]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1>[CH3:44][C:35]1[CH:34]=[C:33]([C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([CH3:43])[CH:41]=2)[N:36]=1
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Reactant: Cc1ccc2nc(C)cc(Cl)c2c1
Agent: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nc(C)cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2c1

Procedure:
First, 3,5-bis(trifluoromethyl)phenylmagnesium bromide prepared from Mg and 3,5-bis(trifluoromethyl)bromobenzene was dropped into a THF solution of 4-chloro-2,6-dimethylquinoline (1 g) andNi(dpp)Cl2 (dpp: 1,3-bis(diphenylphosphino)propane) (0.1 g). Reactions were allowed to take place for 24 hours at room temperature. Water was added to the reaction solution and the organic layer was extracted using CHCl3. The solvent was removed under reduced pressure and the residue was purified through column chromatography to obtain 2,6-dimethyl-4-[3,5-bis(trifluoromethyl)phenyl]quinoline (0.5 g).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:15][CH:16]=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:24])[CH:22]=[O:23])[C:6]([CH3:14])=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[S:11][CH:12]=1)(=[O:3])[CH3:2].[CH3:26][O:27][C:28](=[O:47])[CH2:29][C@H:30]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:31]([CH3:38])([CH3:37])[C:32](=[O:36])[CH:33](Br)[CH3:34]>C1COCC1.[Cl-].[Na+].O>[CH3:26][O:27][C:28](=[O:47])[CH2:29][CH:30]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[C:31]([CH3:37])([CH3:38])[C:32](=[O:36])[CH:33]([CH3:34])[CH:22]([OH:23])[CH:21]([CH3:24])[CH2:20][CH2:19][CH2:18][C:17]([CH3:25])=[CH:16][CH2:15][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([CH3:14])=[CH:7][C:8]1[N:9]=[C:10]([CH3:13])[S:11][CH:12]=1
Reactant: COC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)Br
Reactant: CC(=O)OC(CC=C(C)CCCC(C)C=O)C(C)=Cc1csc(C)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC(OC(C)=O)C(C)=Cc1csc(C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 240 mg (1.95 mmol) CrCl2 and 125 mg (0.93 mmol) in 10.0 mL absolute THF was added 322 mg (0.886 mmol) 3-acetoxy-2,6,10-trimethyl-1-(2-methyl-thiazol-4-yl)-11-oxo-undeca-1,5-diene (8 b) in 1.0 mL absolute THF and 384 mg (0.971 mmol) (3S)-6-bromo-3-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-5-oxo-heptanoic acid methyl ester (235) at ambient temperature. After stirring for 2 h 15 min at ambient temperature, 12 mL brine were added and stirring was continued for five minutes. The waterphase was extracted five times with 15 mL of a pentane-diethylether-mixture (1:5) and the combined organic layers were washed twice with 20 mL demi water and twice with 20 mL brine. After drying over Na2SO4, filtration and concentrating in vacuo, the obtained oil was purified by flash chromatography (column dimensions: 2.0×20.0 cm, diethylether/petroleum ether=5:4).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:29]2[CH:28]([C:27](=[O:32])[N:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:34])[F:33])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CCCN1c1ccc(OC(F)(F)F)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C2CN(Cc3ccccc3)CC2CCN1c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To N-benzyl(methoxy)-N-((trimethylsilyl)methyl)methanamine (1.7 g, 7.0 mmol) and 1-(4-trifluoromethoxy-phenyl)-5,6-dihydro-1H-pyridin-2-one (0.6 g, 2.3 mmol) in DCM (30 mL) was added a solution of trifluoroacetic acid (0.026 g, 0.23 mmol) in DCM (10 mL) at 4° C. After the mixture was stirred at 50° C. for 3 h, the solution was washed with saturated sodium bicarbonate and brine, then dried over anhydrous Na2SO4. After removal of the DCM, the residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate P (10:1 to 5:1) to yield the title compound (0.19 g, 21%). 1H NMR (300 MHz, CDCl3): δ 7.34-7.20 (m, 9H), 3.77-3.55 (m, 4H), 3.18-3.01 (m, 2H), 2.93-3.83 (m, 3H), 2.43-2.41 (m, 1H), 2.07-2.05 (m, 1H), 1.80-1.75 (m, 1H); LC-MS: [M+1]+ 391.1.
Reaction SMILES: [C:1]1(=[O:15])[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH2:2]1.[Br:16]Br.O>C(O)(=O)C>[Br:16][CH:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][N:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12]3)[C:1]1=[O:15]
Reactant: BrBr
Reactant: O=C1CC=Cc2ncc3ccccc3c21
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2c(ncc3ccccc23)C=CC1Br
Yield: 91.4 %

Procedure:
99.8 g (511 mmol) phenanthridinone was added to a 3 L multi-neck flask equipped with a stir arm and condenser. 1.2 L glacial acetic acid was added and the mixture was allowed to stir at 150 rpm and heated to reflux. 90 g (562 mmol) Br2 suspended in 100 ml acetic acid was added to the refluxing solution dropwise over a period of 3 hours. After addition, the mixture was assayed and revealed to be ˜80% complete. Based on this assay, an additional 20 g of Br2 (in 30 mL acetic acid) was added dropwise to the mixture at reflux. After this addition, the assay was >90% complete. A final 20 g Br2 (in 30 mL acetic acid) was added dropwise and the mixture allowed to stir for 1 hour after addition. The final assay was >97%. The mixture was cooled and 1 L of water was added and the mixture filtered. The wet solids were then stirred in aqueous sodium thiosulfate to destroy residual bromine and refiltered. These solids were rinsed with H2O and allowed to dry in vacuo to remove residual water. The solids were then recrystalllized from nitrobenzene (>2 liters) and collected on a funnel to give 128 g 2-bromophenanthridinone (90.8% yield).
Reaction SMILES: C1(C)C(C)=CC=CC=1.Cl.[NH2:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[C:13]([F:19])[C:12]=1[SH:20].[CH2:21]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#N)[CH3:22]>C(O)C>[CH2:21]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[S:20][C:12]2[C:13]([F:19])=[CH:14][C:15]([F:18])=[C:16]([F:17])[C:11]=2[N:10]=1)[CH3:22]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: CCOC(=O)CCCCCC#N
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCCCc1nc2c(F)c(F)cc(F)c2s1
Yield: 39.7 %

Procedure:
To xylene (6 ml) was added 2-amino-3,4,6-trifluorothiophenol hydrochloride (647 mg, 3 mmol), 6-cyanohexanoic acid ethyl ester (507 mg, 3 mmol) and ethanol (0.5 ml) and the mixture was heated to reflux for 60 hours under a nitrogen stream. The resultant reaction mixture was washed with water, dried and then evaporated to yield a residue, which was purified on a silica gel column to give 6-(4,5,7-trifluorobenzothiazol-2-yl)hexanoic acid ethyl ester (395 mg, 40%) as an oil.
Reaction SMILES: CC(C)=O.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[S:21]>O>[CH3:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:20](=[S:21])[O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=1
Reactant: CNc1ccccc1
Reactant: CC(C)(C)c1cc(OC(=S)Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C(=S)Oc1ccc(Cl)c(C(C)(C)C)c1)c1ccccc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To 20 ml of acetone were added 1.07 g of N-methylaniline and 1.38 g of anhydrous potassium carbonate, and a solution obtained by dissolving 2.63 g of O-3-tert-butyl-4-chlorophenyl chlorothioformate into 20 ml of acetone was added thereto with stirring at room temperature. After stirring for 30 minutes as it is, the mixture was subjected to refluxing with heating for 2 hours. The reaction mixture was cooled down to room temperature and then poured into cold water. The product was extracted with benzene. The benzene solution was washed with water and a saturated aqueous solution of sodium chloride in this order, and dried over anhydrous magnesium sulfate. Thereafter, benzene was distilled off. The residue was purified through a column chromatography (employing silica gel as carrier, and benzene/hexane=1/1 (V/V) as developing solvent) and further recrystallized form ethanol to give 2.64 g of O-3-tert-butyl-4-chlorophenyl N-methyl-N-phenylthiocarbamate, having melting point of 65°-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].C(N(CC)CC)C.[Cl:19][C:20]1[N:29]=[C:28](Cl)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]#[N:32])[CH:26]=2)[N:21]=1>CC(O)C>[Cl:19][C:20]1[N:29]=[C:28]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]#[N:32])[CH:26]=2)[N:21]=1
Reactant: N#Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: COc1ccc(CN)cc1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Yield: 86.7 %

Procedure:
3.9 g of 3-chloro-4-methoxybenzylamine, 3.97 g of triethylamine and 200 ml of 2-propanol were added to 4 g of 2,4-dichloro-6-cyanoquinazoline. The obtained mixture was refluxed for 30 minutes, cooled to room temperature and filtered to recover a crystalline precipitate. The precipitate was washed with water and chloroform successively to give 5.563 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[C:12]([C:15]1[O:19][CH:18]=[N:17][C:16]=1[CH3:20])(=[O:14])[CH3:13].O>C(OCC)C>[CH3:20][C:16]1[N:17]=[CH:18][O:19][C:15]=1[C:12]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)([OH:14])[CH3:13]
Reactant: Brc1ccsc1
Reactant: CC(=O)c1ocnc1C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ncoc1C(C)(O)c1ccsc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Bromothiophene (4.23 g) in diethylether (10 ml) was added dropwise to n-butyllithium (2.5M solution in hexane, 10.4 ml) in dry diethylether (20 ml) at -70° C. under a nitrogen atmosphere. After 3 hours 5-acetyl-4-methyloxazole (2.5 g) in diethylether (10 ml) was added dropwise. After a further 2.5 hours at -70° C., the mixture was allowed to warm to room temperature and then left overnight. The mixture was poured into water and extracted with ether. The product thus obtained was crystallised from diethylether to give 1-(4-methyl-5-oxazolyl)-1-(3-thienyl)ethanol, m.p. 87°-89° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH3:36])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([NH:28][CH:29]([CH2:40][CH:37]2[CH2:39][CH2:38]2)[C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH3:36])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nc(C)c(CNC2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc(C)c(C(CC2CC2)NC2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 25 h
Yield: 99.4 %

Procedure:
Sodium triacetoxyborohydride (1.80 g, 8.49 mmol) is added to a stirred solution of 4-{[(2,4-dimethyl-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.71 g, 5.25 mmol), cyclopropanecarboxaldehyde (0.44 ml, 5.89 mmol), acetic acid (0.32 ml, 5.59 mmol), and 1,2-dichloroethane (35 ml). The reaction is stirred for 25 h at room temperature under nitrogen. The reaction is poured into 2N NaOH (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 40% ethyl acetate/hexanes to yield (1.98 g, 99%) of 4-{[cyclopropylmethyl-(2,4-dimethyl-thiazol-5-ylmethyl)]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=380.3 (M+1); 1H NMR (CDCl3): δ=4.18 (2H, brs), 3.74 (2H, s), 2.86-2.78 (1H, m), 2.70-2.60 (5H, m), 2.41 (2H, d), 2.32 (3H, s), 1.81-1.70 (2H, m), 1.50-1.39 (11H, m), 0.87-0.80 (1H, m), 0.53-0.46 (2H, m), 0.12-0.06 (2H, m).