Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]([CH3:9])([CH3:8])[C:6]#[CH:7])(=O)C.[N:10]1([C:16]([O:18]C(C)(C)C)=O)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[OH-].[Na+].N>O1CCCC1.C(OCC)(=O)C>[CH3:6][C:5]([CH3:9])([CH3:8])[C:16]([N:10]1[CH2:11][CH2:12][N:13]([C:5]([CH3:8])([CH3:9])[C:6]#[CH:7])[CH2:14][CH2:15]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CC(C)(C)OC(C)=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC(C)(C)N1CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 157 %

Procedure:
0.756 g (6 mmol) of 1,1-dimethylprop-2-yn-1-yl acetate (J. Org. Chem. 1994, 59, 2282-4) and 2.235 g (12 mmol) of 1,1-dimethylethyl piperazine-1-carboxylate are dissolved in 9 ml of tetrahydrofuran and then 0.059 g (0.6 mmol) of cuprous chloride is added. The mixture is heated at reflux for 3 hours. After cooling to ambient temperature, 100 ml of ethyl acetate, 10 ml of 1N aqueous sodium hydroxide and 2 ml of 30% ammonia are added. The organic phase is separated off and washed with 2 times 10 ml of water and then with 10 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated. The product is purified by chromatography on silica gel, eluting with an 85/15 then 75/25 and 65/35 mixture of cyclohexane and ethyl acetate, to give 1.19 g (4.71 mmol) of product in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][SH:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>O.C(O)C>[CH2:12]([S:7][CH2:6][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[CH:11]=[CH2:10]
Reactant: CC(CS)C(=O)O
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCSCC(C)C(=O)O
Temperature: 0 °C

Procedure:
3-Allylsulfanyl-2-methyl-propanoic acid was prepared as described by Zhou et al. J. Org. Chem. 2004, 69, 7072. An ice-cold mixture of 2-methyl-3-sulfanyl-propanoic acid (5 g, 42 mmol) and sodium hydroxide (3.33 g, 83 mmol) in water (50 mL) was treated with a solution of allyl bromide (5.98 g, 49 mmol) in ethanol (100 mL) over 30 minutes. Ice bath was removed after 45 minutes and after 14 hours at room temperature, volatiles were removed under reduced pressure. The residue was cooled in ice, acidified to pH 6 with 1N HCl and extracted with ethyl acetate, washed with water, dried over MgSO4, concentrated under reduced pressure and dried in vacuo at room temperature for 14 hours to leave a clear liquid. Acidification of the aqueous layer to pH 4 afforded an additional 2.7 g of material. Total yield 4.44 g (74%): IR (KBr thin film) 1708 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.83-5.73 (m, 1H), 5.14-5.13 (m, 1H), 5.10-5.09 (m, 1H), 3.15 (d, J=7.3 Hz, 2H), 2.80 (dd, J=13.2, 7.0 Hz, 2H), 2.69 (sextet, J=7.1 Hz, 1H), 2.53 (dd, J=12.8, 6.5 Hz, 1H), 1.28 (d, J=7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 179.01, 131.63, 114.92, 37.38, 32.72, 31.00, 14.19; EIMS m/z 160.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:20])[C:17]([OH:19])=[O:18])=[C:11]([N+:21]([O-:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25]O>>[CH3:25][O:18][C:17](=[O:19])[C:16](=[O:20])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)C(=O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: CO
Agent: Cl
Product: COC(=O)C(=O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 71 %

Procedure:
3-(4-Benzyloxy-2-nitrophenyl)-2-oxopropanoic acid (40 g; 0.127 mole) was dissolved in methanol (300 ml). Hydrochloric acid (conc, 10 ml) was added under stirring. The reaction mixture was heated to reflux for 3.5 hours and then evaporated to dryness. Dichloromethane and water were added to the residue and the phases were separated. The organic phase was washed with diluted sodium hydrogencarbonate solution and water, and dried with magnesium sulfate. Filtration through a short silica gel column and evaporation gave 29.6 g (71% yield) of 3-(4benzyloxy-2-nitrophenyl)-2-oxopropanoic acid methyl ester as a yellow solid.
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].CO.[OH-].[Na+]>O>[CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3cccc(OC)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)c1
Temperature: 50 °C

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 3-(isopropyl(methyl)amino)-2-(3-methoxyphenyl)quinoxaline-6-carboxylate (50 mg, 0.14 mmol, 1.00 equiv), methanol (10 mL), sodium hydroxide (27.4 mg, 0.69 mmol, 5.00 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 20 mg (41%) of 3-(isopropyl(methyl)amino)-2-(3-methoxyphenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=O)[C:3]([NH2:5])=[O:4].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[NH2:18][C:16]1[S:17][C:2]([C:3]([NH2:5])=[O:4])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:15]=1
Reactant: NC(=O)C(Br)C(=O)c1ccccc1Cl
Reactant: NC(N)=S
Solvent: CCO
Product: NC(=O)c1sc(N)nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
A mixture of 2.33 g (8.43 mmole) of 2-bromo-3-(2-chloro-phenyl)-3-oxo-propionamide, 0.77 g (10.11 mmole) of thiourea and 20 mL of ethanol was stirred at room temperature for 18 hours. The mixture was then concentrated under reduced pressure. The residue was purified by chromatography on C18 reverse phase silica gel, eluting with acetonitrile-water (gradient 0:100-50:50) to give 0.72 g of 2-amino-4-(2-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.20).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([O:19]CC4C=CC=CC=4)[CH:18]=3)[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(CC)CC)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([OH:19])[CH:18]=3)[C:13]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Reactant: Nc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-5-benzyloxy-benzoic acid (500 mg), PyBroP (1.2 eq.), aniline (1.1 eq.), and triethylamine (2 eq.) were combined in dichloromethane (5 mL) and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. White solid which precipitated in dichloromethane layer was collected by filtration (493 mg). This material was dissolved in THF and hydrogenated over 10% Pd/C (50 mg) in Parr apparatus for 5 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to yield 362 mg of title compound (76% yield after 2 steps).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]2[C:15]=1[CH:16]([CH3:18])[CH3:17]>[O-2].[O-2].[Mn+4].C(OCC)C>[CH:16]([C:15]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3]=1[CH:2]=[O:1])=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:18])[CH3:17]
Reactant: CC(C)c1c(CO)c(-c2ccccc2)c2c3ccccc3ccn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CC(C)c1c(C=O)c(-c2ccccc2)c2c3ccccc3ccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
A mixture of 2-hydroxymethyl--3-isopropyl-1phenylpyrrolo-[2,1-a]isoquinoline (2.05 g), activated manganese dioxide (22.56 g) and diethyl ether (120 ml) was stirred at the ambient temperature under an atmosphere of argon for 16 hours. The suspension was then filtered, the filtrate was evaporated and the resulting residue was subjected to flash chromatography on silica gel, using as eluent a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (3:1 v/v), to give 3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinoline-2-carboxaldehyde (1.3 g) in the form of a yellow solid, m.p. 134°-136° C. [N.M.R. (in CDCl3): 1.54 (6H, d, J=7 Hz), 4.30 (1H, septet, J=7 Hz), 6.82 (1H, d, J=8 Hz), 7.06-7.54 (9H, m), 7.89 (1H, d, J=8 Hz) and 9.76 (1H, s); Mass spectrum (electron impact) m/e=313].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH:33]=[CH:34][S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[S:35](/[CH:34]=[CH:33]/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:37])=[O:36])[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(N(C3CCN(Cc4ccccc4)CC3)S(=O)(=O)/C=C/c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
A mixture of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (0.10 g, 0.29 mmol), 2-phenyl-ethenesulfonyl chloride (87 mg, 0.43 mmol), and TEA (0.08 mL, 0.57 mmol) in CH2Cl2 (5 mL) was stirred at rt for 20 h. The reaction mixture was concentrated, and the residue was purified on silica gel (60-70% EtOAc/hexanes) to afford the title compound (138 mg, 92%). 1H NMR (500 MHz, CDCl3): 8.12 (s, 1H), 7.50-7.48 (m, 2H), 7.43 (s, 1H), 7.41-7.39 (m, 3H), 7.25 (d, J=6.8 Hz, 2H), 7.20 (t, J=7.0 Hz, 3H), 7.15 (d, J=7.9 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.86 (d, J=15.0 Hz, 1H), 4.13 (t, J=8.0 Hz, 2H), 3.98-3.40 (m, 1H), 3.41 (s, 2H), 3.20 (t, J=8.5 Hz, 2H), 2.87 (d, J=10.5 Hz, 2H), 2.20 (s, 3H), 2.06-2.02 (m, 2H), 1.88 (d, J=10.7 Hz, 2H), 1.61-1.55 (m, 2H). MS: exact mass calculated for C30H33N3O3S, 515.22; m/z found, 516.3 [M+H]+.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([O:26][C@H:27]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:28]3)=[CH:20][C:21](=[O:25])[NH:22]2)=[CH:17][C:16]=1[CH:43]=[CH2:44].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:6]([O:25][C:21]1[CH:20]=[C:19]([O:26][C@H:27]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:28]2)[C:18]2[C:23](=[CH:24][C:15]([O:14][CH3:13])=[C:16]([CH:43]=[CH2:44])[CH:17]=2)[N:22]=1)[CH3:7]
Reactant: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(=O)[nH]c2cc1OC
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(OCC)nc2cc1OC

Procedure:
Triethyloxonium tetrafluoroborate (1.28 g, 6.75 mmol) was added to a solution of the product from step 3 (2.0 g, 4.5 mmol) in DCM (41 mL). DIEA (0.236 mL, 1.35 mmol) was then added after 15 min. After 45 additional min, the reaction mixture was worked up with NaHCO3 and DCM. The organic layer was then dried over MgSO4, and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 10-60% EtOAc/hexanes) to yield the title compound as an oil. LRMS (M+H)+=473.4.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[O:16][CH2:15][CH:12]1[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1
Reactant: COc1ccc2ncnc(OCC3CCC(NCc4ccccc4)CC3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ncnc(OCC3CCC(N)CC3)c2c1

Procedure:
20% Pd(OH)2 on carbon (1 g) was added to a solution of benzyl-[4-(6-methoxy-quinazolin-4-yloxymethyl)-cyclohexyl]-amine (2 g, 5.3 mmol) in MeOH (30 ml) and hydrogenation was carried out under a hydrogen atmosphere (1 bar) at 65° C. The reaction mixture was filtered and the filtrate was concentrated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)([O-])=O>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(Cc2ccc(N)c(N)c2)CC1

Procedure:
1-(3,4-Dinitrobenzyl)-4-methylpiperazine (2.8 g, 10 mmol), was dissolved in DMF:MeOH (1:1, 20 mL) and agitated with 10% Pd/C (280 mg) under an atmosphere of H2 for 12 hrs. The reaction was monitored by TLC. The mixture was then filtered and evaporated to give a dark solid which was used immediately without any further purification.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]([C:22]2([NH:37]C(=O)OC(C)(C)C)[CH2:27][CH2:26][N:25]([C:28]3[C:29]4[CH:36]=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:37][C:22]1([C:20]([NH:19][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH2:16][C:17]#[N:18])=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CC#N)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#CCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
HCl (4M) in 1,4-dioxane (2.011 mL, 8.04 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-2-cyanoethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 114) (0.281 g, 0.54 mmol) in DCM (8 mL) at 20° C. The resulting solution was stirred at 20° C. for 18 hours. The reaction was vacuumed to dryness and was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-2-cyanoethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.096 g, 42.2%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11](N(OC)C)=[O:12])=[CH:9][C:8]([Br:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1)[CH3:19]>C1COCC1>[Br:1][C:2]1[C:10]([C:11]([C:23]2[CH:24]=[CH:25][C:20]([CH2:18][CH3:19])=[CH:21][CH:22]=2)=[O:12])=[CH:9][C:8]([Br:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: CON(C)C(=O)c1cc(Br)c2c(c1Br)CCC2
Reactant: CCc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cc(Br)c3c(c2Br)CCC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.9 %

Procedure:
To a solution of amide 9 (0.27 g, 0.73 mmol) in anhydrous THF (2.7 mL) was added dropwise 4-ethylphenylmagnesium bromide (3.65 mL of 0.5 M in THF, 1.83 mol) at 0° C. under nitrogen atmosphere. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 h. The reaction mixture was quenched with 1 M HCl solution (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 10 (0.25 g, 0.62 mmol, 85%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:21]([O:23]C)=[O:22])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2].[OH-].[Na+].O.Cl>CCO>[C:1]([C:3]1[N:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2]
Reactant: COC(=O)c1nc(C#N)c(-c2ccccn2)c2cc(OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(C(=O)O)nc(C#N)c(-c3ccccn3)c2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 3-cyano-6-methoxy-4-pyridin-2-ylisoquinoline-1-carboxylate (0.04 g, 0.125 mmol) in 3 mL EtOH, was added 0.251 mL 1(N) aqueous NaOH and 1.16 mL water. The reaction was stirred at 0° C. for 4 h and then 1(N) aqueous HCl (0.251 mL) was added. The reaction was warmed up to rt and concentrated to a tan solid (used without further purification).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.[F:21][C:22]1[C:27]([F:28])=[C:26]([C:29]([F:32])([F:31])[F:30])[C:25]([F:33])=[C:24](F)[N:23]=1.CCN(CC)CC>CN(C=O)C>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:24]3[C:25]([F:33])=[C:26]([C:29]([F:31])([F:32])[F:30])[C:27]([F:28])=[C:22]([F:21])[N:23]=3)=[CH:16][CH:15]=2)=[N:3][CH:2]=1
Reactant: Fc1nc(F)c(F)c(C(F)(F)F)c1F
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1nc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)c(F)c(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.6 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (0.27 g, 1.0 mmol), 2,3,5,6-tetrafluoro-4-trifluoromethylpyridine (0.24 g, 1.0 mmol) and DMF (5 mL) were added to a 25 mL round bottom flask equipped with magnetic stirring bar and dry nitrogen line. To the reaction mixture was added Et3N (0.12 g, 1.2 mmol). After stirring 24 h at room temperature, the reaction mixture was concentrated in vacuo, and the residue was partitioned between H2O and EtOAc. The organic layer was concentrated in vacuo and the residue was purified by column chromatography (EtOAc/hexane over SiO2) to afford pteridin-4-yl-{2-[4-(3,5,6-trifluoro-4-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-amine (110 mg) as a beige solid: mp 103-108° C.
Reaction SMILES: [CH3:1][CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH2:4][CH2:3]1.I[CH2:13]C>>[CH2:1]([CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH2:4][CH2:3]1)[CH3:13]
Reactant: CC1CCc2sccc2C1=O
Reactant: CCI
Product: CCC1CCc2sccc2C1=O

Procedure:
Following the procedure for the preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting iodoethane and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.40, 7.07, 3.18–2.96, 2.43–2.27, 2.09–1.94, 1.59, 1.02. HRMS (FAB) calcd for C10H12OS+H 181.0687, found 181.0684. Anal. Calcd for C10H12OS: C, 66.63; H, 6.71. Found: C, 66.50; H, 6.75.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:29]C1C=C(C2C=C(C(O)=O)NN=2)C=CC=1>>[ClH:2].[Cl:29][C:8]1[CH:7]=[C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:21][CH:22]=3)=[O:15])[NH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccc(Cl)cc2)n[nH]1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)n[nH]1
Agent: Cl
Product: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2cccc(Cl)c2)n[nH]1

Procedure:
The title compound was prepared in analogy to Example 1 using (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (prepared in Example 12) instead of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate and 3-(3-chlorophenyl)-1H-pyrazole-5-carboxylic acid (CAS-595610-50-7) instead of 3-phenyl-1H-pyrazole-5-carboxylic acid. White solid. MS (ISP): 383.1 ([M+H]+).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:32])=[O:23])[CH2:17][CH2:16]1.[OH-:33].[NH4+]>O>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH:13]([OH:33])[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:32])=[O:23])[CH2:19][CH2:20]1
Reactant: [OH-]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CCC2COc3ccccc3O2)CC1
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
A solution of 3.5 g of 1-[2-(1,4-benzodioxan-2-yl)ethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrochloride salt in water (50 ml) is adjusted to pH 12 with ammonium hydroxide solution and extracted with methylene chloride. The methylene chloride is evaporated to afford 3 g of 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine as the free base.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O>>[C:15]1([NH:14][C:4](=[O:5])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[F:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccccc1O
Product: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15b), from 2-fluoro-5-nitrobenzoylchloride (2.23 g, 11.0 mmol) and 2-aminophenol (1.20 g, 11.0 mmol) the subtitle compound was obtained (2.89 g, 91%). 1H NMR (DMSO) δ 10.00(s, 1H), 9.75(d, 1H), 8.62(m, 1H), 8.46(m, 1H), 7.96(d, 1H), 7.67(t, 1H), 7.03(t, 1H), 6.94(d, 1H), 6.85(t, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]2[N:11]([C:12]3[N:13]=[C:14]4[CH2:23][O:22][CH2:21][C:15]4=[CH:16][C:17]=3[CH2:18]2)[C@H:10]([CH3:24])[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O.[O-2].[O-2].[Mn+4]>[CH3:24][C@@H:10]1[CH2:9][NH:8][CH2:20][C:19]2[N:11]1[C:12]1[N:13]=[C:14]3[CH2:23][O:22][CH2:21][C:15]3=[CH:16][C:17]=1[CH:18]=2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc4c(nc3N21)COC4
Agent: [Mn+4]
Agent: [O-2]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNCc2cc3cc4c(nc3n21)COC4
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a solution of 0.050 g (5R,8aR)-5-methyl-3,5,6,8,8a,9-hexahydro-1H-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene-7-carboxylic acid tert-butyl ester in 3 ml dichloromethane was added in 4 portions in intervals of 30 min 0.20 g manganese dioxide. The mixture was then stirred at room temperature for 18 h. The product was purified by chromatography on silica gel with heptane:ethyl acetate=1:1. to yield a yellow oil which was taken up in 1 ml trifluoroacetic acid and kept at room temperature for 30 min. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was neutralized to pH 12 by addition of 2N sodium hydroxide and extracted with dichloromethane. The dichloromethane phase was washed with half concentrated brine and purified by chromatography on silca gel with dichloromethane:methanol:ammonia=90:10:0.1. to yield 0.011 g of the title compound as slightly yellow oil. (MS 232.1 (M+H+))