Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.[H-].[Na+]>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C@H:12]([O:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
4-Fluoronitrobenzene (2.82 g, 20 mmol) was mixed with (S)-3-hydroxy-N-Boc-pyrrolidine (3.74 g, 20 mmol) in dry THF (100 mL). At 0° C., sodium hydride (1.69 g, 60% dispensed in mineral oil, 2.20 eq) was added. The mixture was stirred at 0° C. for 60 min and at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and 0.2N hydrochloric acid. The organic layer was washed with brine and dried over sodium sulfate. After the evaporation of solvents, the residue was purified through flash column chromatography using ethyl acetate and hexanes (5% to 60% ethyl acetate) to give a crystalline material as (S)-3-(4-nitro-phenyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.33 g, 70.3% yield).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), 2.0 M methylamine in THF (2.0 ml, 4 mmol) by a procedure similar to that of example 38 (53.7%). 1H NMR (CDCl3): 7.45 (d, J=7.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.11-7.07 (m, 2H), 6.90-6.87 (m, 3H), 6.69-6.64 (m, 1H), 4.95 (brs, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.11 (d, J=5.1 Hz, 3H).
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C)(OC(C)(C)C)=O.[ClH:18].CCOCC>O1CCOCC1>[ClH:18].[CH3:1][NH:8][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(CCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
3-(N-Me,N-nPr Carbamyloxy) N-Boc,N-methyl phenethylamine (6.0 g, 17.14 mmol) was dissolved in dioxane (60 ml) and 20% HCl/ether (60 ml) was added. The mixture was stirred at RT for 4 hrs and evaporated to dryness in-vacuo, and the residual oil was treated with ether (2×150 ml), to give, after stirring and ice-cooling, 4.6 g (93.5%) of the title compound as a white solid. In this manner the compounds shown in Table 2 were prepared, their analytical characteristics are given in Table 4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N)C>>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:10]([OH:14])[C:11](=[O:13])[NH:28][CH2:27][CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:2])[CH3:3]
Reactant: NCCOc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: CCN
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)NCCOc1ccccc1

Procedure:
The reaction was performed as in Reference Example 8 (5) by using (3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-5-methyl hexanoic acid in place of (3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyric acid, and by using 2-phenoxyethylamine in place of an aqueous ethylamine solution, thereby yielding ((1S)-2-hydroxy-1-(2-methylpropyl)-3-oxo-3-(2-phenoxyethyl)aminopropyl carbamic acid 1,1-dimethylethyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-])=[O:5].Cl.C(N=C=NCCCN(C)C)C.[N:22]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>ClCCl>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:5]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: OCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCCCN1CCOCC1

Procedure:
Monomethyl fumarate (MMF) was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (1.2 eq) in dichloromethane (DCM) at ca. 0° C. 3-Morpholin-4-yl-propan-1-ol (1 eq) and 4-N,N-dimethylaminopyridine (DMAP) (catalytic amount) were added to the activated carboxylic acid. After the completion of the reaction, followed by the work-up of the reaction mixture, the title compound was isolated as a viscous-oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:21][CH2:20]2)=[O:16])=[CH:12][N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)s1

Procedure:
2-[(tert-Butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid was coupled to benzyl 4-(aminomethyl)piperidine-1-carboxylate according to the procedure for EXAMPLE 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([I:16])[CH:4]=1.N1C=CN=C1.[Si:22](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CN(C=O)C>[Si:22]([O:1][CH2:2][C:3]1[C:8]([S:9][CH3:10])=[CH:7][C:6]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])=[C:5]([I:16])[CH:4]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSc1cc(NS(C)(=O)=O)c(I)cc1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1cc(NS(C)(=O)=O)c(I)cc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-(hydroxymethyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide (6.4 g, 17.2 mmol) and imidazole (1.76 g, 25.8 mmol) in CH2Cl2 (100 mL) and DMF (50 mL) at 0° C. was added tert-butyldiphenylsilyl chloride (5.8 mL, 22.4 mmol). The mixture was allowed to stir at rt overnight. The mixture was diluted with CH2Cl2 (100 mL), washed with 1N HCl solution, sat. aq. NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford N-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide. It was used for next step without further purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1>[OH-].[Na+].C(O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: CCOC(=O)CNC1CCc2ccc(C(F)(F)F)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC1CCc2ccc(C(F)(F)F)cc2CC1
Yield: 87 %

Procedure:
315.34 g (1 mol) of 2-trifluoromethyl-7-(N-ethoxycarbonylmethylamino)-6,7,8,9-tetrahydro-[5H]-benzocycloheptene are heated at reflux for approximately 25 minutes in a mixture of 1000 ml of normal sodium hydroxide and 2200 ml of ethanol. The ethanol is then distilled off terminating under reduced pressure, and the aqueous phase is washed twice with 4000 ml of diethyl ether each time. The ethereal phases are washed with water again. 1000 ml of a normal hydrochloric acid solution are added to the combined aqueous phases. The precipitate obtained is collected and washed. 250 g of 2-trifluoromethyl-7-(N-carboxymethylamino)-6,7,8,9-tetrahydro-[5H]-benzocycloheptene are obtained, which sublimes above 260° C. (Yield 87%). By adding a stoichiometric amount of hydrochloric acid and recrystallising from water, the hydrochloride of this amino acid, which sublimes towards 220°-222° C., is obtained.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36])=[C:30]([CH3:39])[CH:29]=1.Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:38][C:35]([CH3:36])([CH3:37])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[CH3:39])[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(F)ccc1CC(C)(C)N
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Agent: Cl
Product: Cc1cc(F)ccc1CC(C)(C)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
Prepared analogously to the method for Example 8(d) from 0.95 g (2.66 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.43 g (2.37 mmol) of 2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamine. Yield: 0.75 g (55%, hydrochloride); melting point 233° C.-236° C.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5][NH2:6].[CH3:12][S:13][C:14](SC)=[N:15][C:16]#[N:17]>C(O)C>[C:16]([NH:15][C:14](=[N:6][CH2:5][CH2:4][CH2:3][C:2]([F:11])([F:1])[C:7]([F:8])([F:9])[F:10])[S:13][CH3:12])#[N:17]
Reactant: NCCCC(F)(F)C(F)(F)F
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NCCCC(F)(F)C(F)(F)F)NC#N
Yield: 69.3 %

Procedure:
A solution of 4,4,5,5,5-pentafluoropentylamine (0.118M, 30 ml, 3.55 mmole) and of dimethyl N-cyanodithioiminocarbonate (700 mg, 4.26 mmole) in ethanol (30 ml) was heated under reflux for 18 hours. Concentration under reduced pressure, followed by crystallization from ethyl acetate and petroleum ether afforded 1-cyano-3-(4,4,5,5,5-pentafluoropentyl)-2-methylisothiourea (677 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](N(OC)C)=[O:13])[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:25][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:13])[CH3:25])[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-chloro-8-(2-fluorophenyl)-N-methoxy-N-methylquinoline-7-carboxamide (40 mg, 0.1 mmol) in tetrahydrofuran (0.2 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.50 mL, 0.70 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was used directly in next step (32 mg, 92%). LCMS calculated for C17H12ClFNO(M+H)’ : m/z=300.1; found: 284.0.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:22][C:21]([CH2:24][OH:25])([OH:23])[CH2:20]3)=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1>CN(C)C=O>[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:20][C:21]([CH2:24][OH:25])([OH:23])[CH2:22]3)=[N:17][C:18]=2[I:1])[CH:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: OCC1(O)CC(c2ncc3c(Cl)nccn23)C1
Solvent: CN(C)C=O
Product: OCC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 60 °C

Procedure:
Under inert atmosphere N-iodosuccinimide (3.6 g, 0.016 mol) and 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethylcyclobutanol (3.16 g, 0.012 mol) were dissolved in N,N-dimethylformamide (30 mL) and heated at 60° C. for 3.0 h. The reaction mixture was then concentrated in vacuo to a dark oil and purified by HPFC Jones 20 g silica gel column, eluting with 5% MeOH: CH2Cl2 to yield a light brown fluffy solid which was triturated with diethyl ether and hexanes to afford the title compound; MS (ES+): m/z 379.85 and 381.80 [MH+]; HPLC: tR=2.30 min (OpenLynx, polar—5 min).
Reaction SMILES: C(OC(=O)C[N:6]1[N:10]=[N:9][C:8]([C:11]2[S:15][C:14]([Br:16])=[N:13][CH:12]=2)=[N:7]1)C.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20](=[O:21])[CH2:19][N:10]1[N:6]=[N:7][C:8]([C:11]2[S:15][C:14]([Br:16])=[N:13][CH:12]=2)=[N:9]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)Cn1nnc(-c2cnc(Br)s2)n1
Product: CC(C)(C)OC(=O)Cn1nnc(-c2cnc(Br)s2)n1

Procedure:
This compound was synthesized in a similar manner as described for ethyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (INTERMEDIATE 2) using tert-butyl bromoacetate in place of ethyl bromoacetate in step 4. 1H NMR (CDCl3, 400 MHz) 8.22 (1H, s), 5.32 (2H, s), 1.47 (9H, s). MS (ESI, Q+) m/z 346, 348 (M+1, 79Br, 81Br).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:15])SC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](#[N:18])[CH3:17]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([N:18]1[CH2:5][CH2:4][CH:3]([CH2:2][CH2:1][OH:8])[CH2:17][CH2:16]1)=[NH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Reactant: CC#N
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CCO)CC1
Yield: 41 %

Procedure:
(0.028 mol) of N-benzyloxycarbonyl-S-methyl isothiourea in 50 ml of acetonitrile was refluxed overnight. Evaporation and flash chromatography on silica gel with ethyl acetate gave 3.5 g (41%) of the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].[NH3:11]>CC(C)=O>[CH3:1][C:2]1([CH3:3])[NH:11][C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4]1
Reactant: CC(C)=CC(=O)C=C(C)C
Reactant: N
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 70 %

Procedure:
Heinz Annalen der Chemie 203 336 (1880) converts acetone to phorone in about 30% yield, and reacts phorone with ammonia to form triacetone amine in 70% yield.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:14]2[CH:15]=[C:16]([C:19](Cl)=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10]1.[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:42]2[N:38]([CH:39]=[C:40]([CH3:47])[C:41]=2[O:45][CH3:46])[CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:42]2[N:38]([C:39]([C:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:12]=[C:11]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[O:10][C:9](=[O:8])[C:14]=4[CH:15]=3)=[O:20])=[C:40]([CH3:47])[C:41]=2[O:45][CH3:46])[CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)c1ccc2nc(-c3ccccc3)oc(=O)c2c1
Reactant: COc1c(C)cn2cc(OCc3ccccc3)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2cc(OCc3ccccc3)ccc12
Reaction time: 2 h
Yield: 71.9 %

Procedure:
10 ml (71.8 mmol) of triethylamine and 15 g (52.7 mmol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carbonyl chloride are added portionwise, at ambient temperature and under nitrogen, to the solution of 12.8 g (47.9 mmol) of 6-(benzyloxy)-1-methoxy-2-methylindolizine in 160 ml of dichloromethane. The reaction medium is stirred for 2 hours and is then filtered. The solid obtained is washed with dichloromethane and then with diisopropyl ether and dried. 17.8 g (83%) of an orange powder are obtained.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[B-](F)(F)(F)[F:15]>>[F:15][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: F[B-](F)(F)F
Reactant: COc1ccc(C(F)(F)F)cc1N
Product: COc1ccc(C(F)(F)F)cc1F

Procedure:
The 2-amino-4-trifluoromethylphenols (XI) required for the reaction sequence just described may be prepared by conventional methods. Thus, 2-amino-6-fluoro-4-trifluoromethylphenol may be prepared from 2-nitro-4-trifluoromethylchlorobenzene by reacting the latter with sodium methoxide to give 2-nitro-4-trifluoromethylanisole, and reducing this compound to 2-amino-4-trifluoromethylanisole. The latter compound may be diazotised and converted to its fluoborate salt and heated to give 2-fluoro-4-trifluoromethylanisole. This may then be nitrated to form 2-fluoro-6-nitro-4-trifluoromethylanisole, which is then reduced to give 2-amino-6-fluoro-4-trifluoromethylanisole. Finally the latter compound is heated with a demethylating agent, for example an excess of pyridine hydrochloride to give 2-amino-6-fluoro-4-trifluoromethylphenol.
Reaction SMILES: [CH2:1]([C:4]1([CH:19]=[CH:20][O:21]C2CCCCO2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([C:4]1([CH2:19][CH:20]=[O:21])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(C=COC2CCCCO2)c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(CC=O)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Dissolved 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl-(2-tetrahydropyranyloxy-ethene) (4.82 g, 13.37 mmol) in 50 mL of THF. Added 50 mL of 0.2N HCl, and refluxed for 18 hours. Cooled to room temperature, and added 150 mL of saturated NaHCO3. Extracted with ethyl acetate. Washed combined organic extracts with saturated NaCl, dried (MgSO4), filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 10% ethyl acetate-hexane. Combined appropriate fractions and evaporated to give 3.32 g (90% yield) of 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-ethanal).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([OH:26])[CH2:22][C:21]2[CH:20]=[C:19]3[C:10]([C:11](=[O:24])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:23])=[C:9]([OH:25])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:27]([O-:30])(=[O:29])[CH3:28].[Na+]>CC(C)=O>[C:27]([O:30][CH2:2][C:3]([C:5]1([OH:26])[CH2:22][C:21]2[CH:20]=[C:19]3[C:10]([C:11](=[O:24])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:23])=[C:9]([OH:25])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:29])[CH3:28]
Reactant: O=C1c2ccccc2C(=O)c2c1cc1c(c2O)CCC(O)(C(=O)CBr)C1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)C1(O)CCc2c(cc3c(c2O)C(=O)c2ccccc2C3=O)C1
Yield: 75.6 %

Procedure:
To a solution of 9-bromoacetyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (780 mg) in acetone (64 ml) was added sodium acetate (1.6 g) and the mixture was allowed to react at room temperature for 65 hours. After removing insoluble matters by filtration, the most part of the solvent was distilled off under reduced pressure and subjected to filtration to give yellow crystals (560 mg, 76%) of 9-acetoxyacetyl6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 203°-206° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>[Pd].ClCCl>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Reaction time: 2 h

Procedure:
A round bottom flask was charged with (S)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (1.3 g, 0.0050 mol),methanol (40 mL, 1 mol), dichloromethane (5 mL) and palladium on charcoal (0.2 g, 0.001 mol) were added and the mixture was stirred under hydrogen (1 atm) for 2 h. The reaction mixture was filtered over celite and the solvent removed under reduced pressure to yield the pure product as an off white solid. MS m/z=232.5 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)CCC>O>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:2]1[CH:7]=[CH:6][C:5]([C:16]2[O:15][CH:14]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Brc1ccc(Br)cc1
Solvent: O
Product: c1coc(-c2ccc(-c3ccco3)cc2)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
To a stirred solution of 1,4-dibromobenzene (5 mmol) was added palladium tetrakis-triphenylphosphine (400 mg). The reaction mixture was kept stirring for 15 min after which 2-tributylstannylfuran (10 mmol) was added and the reaction mixture was refluxed at 100° C. for 24 h. The solvent was then evaporated to dryness to give a dark brown residue that was suspended in water and extracted with CH2Cl2. The organic layer was passed over hyflo, dried (Na2SO4) and evaporated to dryness under reduced pressure to give 15 in 91% yield; mp 149-150° C. 1H NMR (DMSO-d6); δ 6.62 (d, 2H), 7.01 (d, 2H), 7.76-7.79 (m, 6H). MS (ESI) m/e (rel. int.): 210 (M+, 100), 181 (40), 153 (30). Anal. Calc. for C14H10O2: C %, 79.98; H %, 4.79. Found C %, 80.12; H %, 4.59.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cccc(Br)n1
Temperature: 70 °C
Yield: 87.8 %

Procedure:
A suspension of 2-(6-Bromo-pyridin-2-ylmethyl)-isoindole-1,3-dione (4000 mg, 12.61 mmol) in ethanol (60 mL ) was heated at 70° C. until complete dissolution was observed. Hydrazine hydrate (3156 mg, 63.06 mmol) was then added and the resulting mixture was heated at 70° C. for 5 h. The resulting solution was cooled to 0° C. and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by column chromatography with a gradient of 0 to 30% methanol/dichloromethane to give C-(6-Bromo-pyridin-2-yl)-methylamine as a yellow solid (2070 mg, 79%). MS ES (MH+187.1, RT=1.11 min).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[CH:4]=1.CN(C)[CH:13]=[O:14]>C(Cl)Cl>[Br:10][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([Br:9])[CH:6]=1)[CH:13]=[O:14]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
1.344G (56 mM) of magnesium was added to a solution of 15-7G(50 mM) of 1,3,5-tribromobenzene and the mixture was stirred at room temperature after 5 hours, most of the metal was digested. To the resulting brown Grignard solution was added 7.5 mL (0.1M) of N,N-dimethylformamide at 0° under nitrogen. The resulting mixture was stirred overnight at room temperature. Solvent was removed in vacuo at room temperature. The residue was taken up in 200 mL of ethyl acetate and washed with 6×50 mL of saturated sodium chloride solution, dried over anhydrous MgSO4. Solvent was removed to give a crude solid, which was dissolved in minimum amount of CH2Cl2 and applied on silica gel. Elution with 1:9 mixture of ether:hexane containing methylene chloride gave 45% yield of the desired aldehyde as white solid.