Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4]1.Cl[C:25]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][N:33]=2)[CH:28]=[C:27]([Cl:35])[N:26]=1.CCN(C(C)C)C(C)C>C1COCC1>[Si:10]([O:9][CH:7]1[CH2:8][CH:3]([CH2:2][NH:1][C:25]2[C:34]3[C:29](=[N:30][CH:31]=[CH:32][N:33]=3)[CH:28]=[C:27]([Cl:35])[N:26]=2)[CH2:4][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(CN)CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)cc3nccnc23)CC(O[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of tert-butyl 3-(aminomethyl)-5-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (4.74 g, 13.7 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (2.75 g, 13.7 mmol) and DIPEA (2.12 g, 16.4 mmol) in THF (20 mL) was stirred at room temperature for 48 hours. The volatiles were removed under reduced pressure and the residue was treated with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:14])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Br)cc1CO
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Br)cc2CO1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a solution of (2-amino-5-bromophenyl)methanol (772 mg, 3.8 mmol) in 15 ml THF was added triphosgene (1.03 g, 3.8 mmol) under nitrogen. After precipitation of a colorless solid, stirring was continued for 20 min before water was added. The solution was extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 6-bromo-1H-benzo[d][1,3]oxazin-2(4H)-one (830 mg, 3.64 mmol, 96%) as colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[N:16][C:15]=1[CH3:22].[CH3:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCOCC>[OH:30][C:24]([CH3:23])([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][C:15]1[C:14]([CH3:13])=[N:19][C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: CCCCCC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCCCCC(C)(O)Cc1nc(C)c(C)nc1C

Procedure:
The preparation is carried out in the manner described in Example VII using 10.1 grams (0.1 mole) of diisopropylamine in 80 milliliters of ether, 0.95 mole of butyllithium, 13.6 grams (0.1 mole) of tetramethylpyrazine, and 12.8 grams (0.1 mole) of 2-heptanone. The reaction is worked up as before, and the product is isolated by chromatography on silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[H-].[Na+].[CH3:14][O:15][CH2:16]Cl>CN(C)C=O.O>[CH3:14][O:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COCCl
Reactant: Oc1cccc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-hydroxyquinoline (10.3 g) in dimethylformamide (140 ml) was ice-cooled. To the solution was added sodium hydride (3.0 g, 62.6% in oil) and the mixture was stirred at 0° C. for 15 minutes. To the reaction mixture was added methoxymethyl chloride (6.5 ml) and then the mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added ice. The reaction mixture was stirred and then diluted with water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1N aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate, and then concentrated to give the title compound (10.4 g) having the following physical data. The obtained compound was used without purification in the subsequent reaction.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=2)[O:12][CH2:11][CH2:10]1)=[O:7]>C(O)C.O>[Cl:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[O:12][CH2:11][CH2:10]1)=[O:7]
Reactant: COC(=O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
KOH (1 mol/1 aq) (2 eq.) was added to a suspension of methyl 4-(2-chlorobenzamido)chroman-6-carboxylate (B-11) (2.227 mmol, 1 eq.) in a mixture of ethanol (13 ml) and water (4.5 ml). The reaction mixture was stirred at room temperature for 16 h. Ethanol was removed in vacuo and the aqueous residue was diluted with diethyl ether (20 ml) and water (20 ml). The phases were separated and the aqueous phase was acidified with 1N HCl to pH 3. The white precipitate was filtered out, washed with aqueous HCl solution and diethyl ether and finally dried in vacuo to obtain the desired product (E-11). Yield: 85%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C[O:12][C:13](=[O:42])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3Br)[CH:24]=2)=[CH:18][C:17]=1[CH3:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:31]2[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:30]=2[O:29][C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:42])=[O:12])=[C:17]([CH3:41])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccc(F)cc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 4-fluorophenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 129 mg (60%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H22O4F4 510, found 511 (M+1, 100%).
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:7]([N:17]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCN
Reactant: O=C1CCCO1
Product: CCCCCCCCCCN1CCCC1=O
Reaction time: 22 h
Yield: 83.1 %

Procedure:
18.8 g (0.22 M) of γ-butyrolactone and 34.6 g (0.22 M) of n-decylamine were mixed and heated to 180° in a round bottom flask equipped with a condenser and a Dean-Stark trap for 22 hours. The dark brown reaction mixture was distilled at reduced pressure to yield 40.9 g (82.5%) of colorless product; b.p. 150°-155°/0.5-1 mm.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:7][C:8]1[N:9]=[C:10]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Nc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1cccc(Nc2nccs2)n1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 1.37 g (9.26 mmol) of 2-aminothiazole, 0.74 g (7.39 mmol) of 2,6-dichloropyridine, 387 mg (0.621 mmol) of (S)-(−)-2,2′-(bisdiphenylphosphino)-1,1′-binaphthyl, 322 mg (0.311 mmol) of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 2.77 g (8.50 mmol) of cesium carbonate and 10 m1 of toluene was heated under reflux for 1 hour and 30 minutes, cooled to room temperature and diluted with ethyl acetate. An insoluble matter was filtered off using Celite and the resulting ethyl acetate solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography to give 990 mg (4.68 mmol) of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].Cl.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[ClH:17].[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:16][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)c(OCCN2CCOCC2)c1

Procedure:
2-Morpholin-4-yl-5-nitrophenol and 4-(2-chloroethyl)morpholine were allowed to undergo the reaction in DMF in the presence of potassium carbonate, and then the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 and further treated with 4 M hydrogen chloride/ethyl acetate solution in ethyl acetate to obtain 4-morpholin-4-yl-3-(2-morpholin-4-ylethoxy) aniline hydrochloride. F: 308.
Reaction SMILES: C(O)C.Cl.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O=[Pt]=O.O1CCCC1>[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Oc1ccc2cccnc2c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
PtO2 (528 mg, 2.33 mmol) was added to a dry flask. Ethanol (70 mL), tetrahydrofuran (70 mL), and hydrogen chloride (7.6 mL, 2N) were added after the flask was flushed with argon. Quinolin-7-ol (1000 mg, 6.89 mmol) was added into the flask under argon atmosphere. The solution was degassed and flashed with argon. Hydrogen gas was introduced to the flask by a balloon. The mixture was stirred at H2 atmosphere at room temperature overnight. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by MPLC (biotage) to afford 730 mg (71%) of the title compound. 1H-NMR (CDCl3) δ 6.77 (d, J=7.6 Hz, 1H), 6.10 (dd, J=8.0 Hz, 2.8 Hz, 1H), 5.95 (d, J=2.4 Hz, 1H), 3.24 (t, J=5.9 Hz, 2H), 2.66 (t, J=5.9 Hz, 2H), 2.44 (m, 2H); Rf=0.74, 50% ethyl acetate-hexane.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH:21]=1
Reactant: ClCc1cccnc1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cccnc2)c(=O)[nH]c1=O
Yield: 25.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (95 mg, yield: 25.9%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH:12]=[C:11]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:10]=[CH:9]1>[Pd].C(O)(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:10]=[CH:9]1
Reactant: O=C(O)CCCC=Cc1c[nH]cn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCCc1c[nH]cn1
Reaction time: 13 h
Yield: 79.7 %

Procedure:
4 ml of acetic acid and 80 mg of palladium-on-charcoal at 10% are added to 218 mg (0.741 mmol) of 6-(1H-imidazol-4-yl)hex-5-enoic acid trifluoroacetate. The reaction medium is placed under a hydrogen atmosphere at atmospheric pressure. After 13 hours, the reaction medium is filtered through celite. After the solvents have been evaporated off, 175 mg of 6-(1H-imidazol-4-yl)hexanoic acid trifluoroacetate in the form of a yellow oil are obtained with a yield of 80%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:14])[CH2:8][C:9](OCC)=O)[CH2:3][CH2:2]1.[H-].[Na+].ClC1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:28])[CH:21]=[C:20]([C@@H:29]([NH:31][C:32]2[N:40]=[CH:39][N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[CH3:30])[N:19]=1.O>C1COCC1>[Cl:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:9]([CH2:8][C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:14])=[N:19][C:20]([C@@H:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]3[C:33]=1[N:34]=[CH:35][N:36]3[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[CH3:30])=[CH:21]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Reactant: CCOC(=O)CC(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(CC(=O)N5CCOCC5)n4)ncnc32)cc1

Procedure:
To a mixture of ethyl 3-morpholino-3-oxopropanoate 33 (402 mg, 2 mmol, 1.0 eq) and NaH (144 mg, 3 mmol, 1.5 eq) in THF (3 mL) at RT, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (765 mg, 1.6 mmol, 0.8 eq) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-2-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl)-1-morpholinoethanone 34.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1>CN(C)C=O.CCOCC>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([O:4][CH:1]([CH3:3])[CH3:2])=[N:9][CH:10]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)cn1
Temperature: 130 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To isopropanol (11 mL, 143 mmol) under nitrogen at 25° C. was added sodium hydride (95%, 1.94 g, 76.7 mmol) portion wise over 5 minutes. The reaction was stirred for 16 hours and a solution of 2-fluoro-5-bromopyridine (9 g, 51 mmol) in N,N-dimethyl formamide (250 mL) was added over 10 minutes. The resulting mixture was heated at 130° C. for 4 hours and cooled to 25° C. The mixture was diluted with ether (500 mL) and washed with water (600 mL) and brine (300 mL). The organic layer was dried (MgSO4), filtered, and concentrated to provide 10.1 g of the title compound (92%) as light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.25 Hz, 6H) 5.08-5.28 (m, 1H) 6.75 (d, J=8.82 Hz, 1H) 7.86 (dd, J=8.82, 2.57 Hz, 1H) 8.26 (d, J=2.57 Hz, 1H); MS (ESI) m/z 217.9 (M+H)+.
Reaction SMILES: [H-].[Na+].O1CCCC1.[NH2:8][C:9]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:11]([O:13]CC)=O.[N:20]([C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH:30]([CH3:32])[C:29](=[O:33])[N:28]([CH2:34][C:35]#[CH:36])[C:27]=2[CH:37]=1)=[C:21]=[O:22]>C(O)(=O)C>[CH3:32][CH:30]1[C:29](=[O:33])[N:28]([C:34]#[C:35][CH3:36])[C:27]2[CH:37]=[C:23]([N:20]3[C:11](=[O:13])[CH:10]=[C:9]([C:16]([F:17])([F:18])[F:19])[NH:8][C:21]3=[O:22])[CH:24]=[CH:25][C:26]=2[O:31]1
Reactant: C#CCN1C(=O)C(C)Oc2ccc(N=C=O)cc21
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC#CN1C(=O)C(C)Oc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A slurry of 1.4 g. of sodium hydride in 25 ml. of dry tetrahydrofuran (THF) was cooled to -10° C. To the cooled and stirred slurry was added a solution of 10.0 g. of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 50 ml. of THF. The addition of this solution was made over a period of 30 minutes. The resultant light brown reaction mixture was cooled to -70° C. A solution of 13.3 g. of 6-isocyanato-2- methyl-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine in 75 ml. of THF was added to the chilled reaction mixture over a period of 10 minutes. After stirring at -70° C. for 30 minutes, the temperature was allowed to rise slowly to 10° C. At that point 3.6 ml. of acetic acid was added to the mixture. A beige solid precipitated. 19.0 Grams of the solid was recovered by filtering it from the reaction mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Cl[C:28]([O:30][CH3:31])=[O:29]>CC(C)=O>[CH3:31][O:30][C:28](=[O:29])[NH:20][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: CCOc1ccc(C#Cc2ccc(C(C)N)cc2)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1ccc(C#Cc2ccc(C(C)NC(=O)OC)cc2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To 26.5 mg (0.10 mmol) 1-[4-(4-ethoxy-phenylethynyl)-phenyl]-ethylamine (I63) in 2.00 mL acetone are added 47.7 mg (0.45 mmol) Na2CO3 and 10.2 μL methyl chloroformate. The reaction mixture is stirred at 40° C. for 3 h. After cooling down to r.t. the reaction mixture is filtered and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [Mg].II.Br[C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15].CN([CH:21]=[O:22])C>C1COCC1>[CH2:16]([CH:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[CH:21]=[O:22])[CH3:17]
Reactant: CCCCC(CC)Cc1ccsc1Br
Reactant: CN(C)C=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1ccsc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture of magnesium turnings (0.61 g, 25.1 mmol), anhydrous THF (20 mL) and a small amount of iodine in a 300 mL flask, a solution of bromothiophene (9-5), (6.58 g, 23.9 mmol) in anhydrous THF (35 mL) was added slowly at 0° C. under N2. After refluxing for 1 h, the reaction mixture was transferred into a 250 mL flask at room temperature under N2. DMF (3.24 mL, 41.9 mmol) was added dropwise to the reaction mixture. After the mixture was stirred overnight at room temperature, the reaction was quenched by pouring cold HCl aq. (2 N) into the mixture. The product was extracted with CHCl3 and dried over anhydrous Mg2SO4. The crude product was further purified by column chromatography using hexane/CHCl3 (2:1) as the eluent to give (9-6) as a colourless oil (3.7 g, 69%). 1H NMR (CDCl3, 300 MHz, ppm): 10.03 (s, 1H), 7.64 (d, 1H, J=5.1 Hz), 6.98 (d, 1H, J=5.1 Hz), 2.89 (d, 2H, J=7.2 Hz), 1.56-1.64 (m, 1H), 1.27-1.37 (m, 8H), 0.86-0.91 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1.[CH3:19][CH:20]1[O:25][CH:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>C(#N)C>[CH3:26][CH:24]1[CH2:23][N:22]([CH2:2][C:3]2[CH:7]=[CH:6][N:5]([C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=2)[CH2:21][CH:20]([CH3:19])[O:25]1
Reactant: CCOC(=O)c1cccnc1-n1ccc(CCl)n1
Reactant: CC1CNCC(C)O1
Solvent: CC#N
Product: CCOC(=O)c1cccnc1-n1ccc(CN2CC(C)OC(C)C2)n1
Yield: 103.3 %

Procedure:
Ethyl 2-(3-(chloromethyl)-1H-pyrazol-1-yl)nicotinate (650 mg, 2.446 mmol), 2,6-dimethylmorpholine (0.482 mL, 3.91 mmol) and K2 CO3 (1082 mg, 7.83 mmol) in acetonitrile (25 mL) were stirred over night at room temperature. The mixture was concentrated, the remaining solid partitioned between 60 mL of water and dichloromethane, the organic layer separated, dried (MgSO4), filtered and concentrated again to yield 870 mg of the title compound as clear oil; ESI-MS [M+H]+: 345.2.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1>C(Cl)Cl>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3C(CN4)C[C@H]2N(C)C1
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
One millimole of 3-(2,3-dihydro-6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea is dissolved in 10 ml of methylene chloride, and 2 g of pyrolusite in solid form is added thereto. The mixture is then stirred for 2 hours at room temperature. After removing excess pyrolusite by filtration, the filtrate is evaporated. The residue is chromatographed on silica gel with methylene chloride/methanol (5%), thus obtaining 210 mg of 3-(6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([O-:20])=O)=[CH:16][N:15]=1.[NH2:23][OH:24].[OH-].[Na+]>O1CCOCC1>[OH:24][NH:23][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([N:2]2[CH2:3][CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[N:15][CH:16]=1
Reactant: NO
Reactant: O=C([O-])c1ccc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NO)c1ccc(N2CCc3c([nH]c4ccccc34)C2)nc1
Reaction time: 0.25 h

Procedure:
A solution of 6-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)nicotinate (12 mg) in dioxane (1.5 mL) was treated with 50% aqueous hydroxylamine (0.2 mL). After 15 minutes, 1N sodium hydroxide (0.06 mL) was added and the reaction was stirred for 72 hours. The reaction was quenched with 1N hydrochloric acid (0.06 mL) and the solvent evaporated. The residue was purified by preparative hplc and the pure samples freeze dried to give N-hydroxy-6-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)nicotinamide as a yellow solid (4 mg), m/e=308 (M+1). 1H NMR (DMSOd6) ppm: 2.8 (2H, m), 4.05 (2H, m), 4.85 (2H, s), 6.9-7.08 (3H, m), 7.29 (1H, d), 7.39 (1H, d), 7.87-7.91 (1H, m), 8.5 (1H m), 10.9 (1H, s), 11.05 (1H, bs).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([NH:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc(Br)c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(Br)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-bromo-phenyl)-thiazol-2-ylamine hydrobromide with 0.31 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.40 g of N-[4-(3-bromo-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.