Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[CH:23]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[S:25][CH:26]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[S:25][CH:26]=[C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])[CH:23]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2cc(C(=O)C(F)(F)F)cs2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2cc(C(=O)C(F)(F)F)cs2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 30 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(4-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 30%). 1H NMR (400 MHz, DMSO-d6) δ 8.21-8.16 (m, 1H), 8.11-8.10 (m, 1H), 8.02-7.96 (m, 3H), 7.91-7.90 (m, 1H), 7.88-7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.67-7.48 (m, 2H), 7.31-7.25 (m, 2H), 3.56-3.54 (m, 2H), 1.33 (d, J=2.1 Hz, 6H). MS (ESI) m/z: Calculated for C26H20F4N2O3S: 516.11. found: 515.7 (M−H)−.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>CN(C)C=O>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC(F)(F)F)C1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 51, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (73%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:15]>[Ni]>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=C1CCN(CC2CCCCC2)CC1
Agent: [Ni]
Product: NC1CCN(CC2CCCCC2)CC1
Reaction time: 3.5 h

Procedure:
A solution of 1-cyclohexylmethylpiperid-4-one (65 g; 0.33 moles in a saturated ethanolic solution of ammonia (350 ml) was hydrogenated in the presence of Raney nickel catalyst (6.5 g) at 75° C. and 13 atmospheres for 3.5 hours. The mixture was cooled, the catalyst filtered off and the solvent removed by distillation in vacuo. The residue was treated with a saturated ethanolic solution of hydrogen chloride, and the insoluble dihydrochloride was filtered off, treated with an aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was dried (Na2SO4) and the solvent removed in vacuo giving 1-cyclohexylmethyl-4-aminopiperidine (45.5 g) as a viscous liquid, b.p. 105°-110° C./0.3 mm Hg.
Reaction SMILES: [NH2:1]/[C:2](=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.O.[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32](=[CH2:35])[CH:33]=O)=[CH:29][CH:28]=1>CCCCO>[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32]2[CH:35]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:1][CH:33]=2)=[CH:29][CH:28]=1
Reactant: C=C(C=O)Cc1ccc(F)cc1
Reactant: CCOC(=O)/C=C(\N)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of diethyl 2-aminofumarate (153 g, 0.81 mol) and p-TsOH.H2O (1.5 g, 8.1 mmol) in n-BuOH (325 mL) was added 2-(4-fluorobenzyl)propenal (162 g, 0.98 mol) dropwise at 120° C. The mixture was stirred for 17 h at 120° C. and at rt for ca. 24 h. The mixture was filtered and concentrated under vacuum to yield the crude diethyl 5-(4-fluorobenzyl)-2,3-pyridinedicarboxylate. This material was dissolved in EtOH (400 mL) and an ice-cold solution of NaOH (88 g, 2.2 mol) in water (300 mL) was added. The mixture was stirred for 2 h at rt. After removal of EtOH in vacuo, water (400 mL) and 6N HCl (200 mL) were added and the mixture was extracted with EtOAc. The EtOAc layer was washed with water and the combined aqueous layers adjusted to pH 2 with 6N HCl (175 mL). The mixture was stirred for 1 h at ice-bath temperature and the product was collected by filtration: 1H NMR (d6-DMSO) δ 8.64 (1H, d, J=2 Hz), 8.01 (1H, d, J=2 Hz), 7.32 (2H, dd, J˜9, 6 Hz), 7.12 (2H, t, J˜9 Hz), 4.05 (2H, s); ES+ MS: 276 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.CC(C)([O-])C.[K+]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of 7-bromoisoquinolin-1(2H)-one (300 mg, 1.34 mmol) and 1-(bromomethyl)-4-fluorobenzene (380 mg, 2.01 mmol) in THF (8 ml) was added potassium t-butoxide (300 mg, 2.68 mmol) and tetrabutylammonium iodide (50 mg, 0.13 mmol). The resulting mixture was stirred at RT for 3 h. The solid was removed by filtration, then concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-30% EtOAc/DCM) to provide 7-bromo-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (410 mg, yield: 92%) (M+H)+: 333.
Reaction SMILES: [ClH:1].Cl.FC1C=CC(C[N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=[C:12]2CC2CCNCC2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.CS(OCCC1SC=CC=1)(=O)=O>O>[ClH:1].[ClH:1].[N:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[NH:11][CH:12]=1
Reactant: Fc1ccc(Cn2c(CC3CCNCC3)nc3cccnc32)cc1
Agent: CS(=O)(=O)OCCc1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: c1cnc2[nH]cnc2c1

Procedure:
A mixture of 7.9 parts of 3-[(4-fluorophenylmethyl]-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine dihydrochloride, 8.5 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 30 minutes using a water separator. 7.8 Parts of 2-thiopheneethanol methanesulfonate (ester) were added and the whole was stirred and refluxed for 4 hours using a water separator. After cooling, the salts were filtered off, washed with 4-methyl-2-pentanone and the filtrate was washed with water. The organic layer was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2-propanone. The salt was filtered off and dried in vacuo at 60° C., yielding 8.0 parts (76%) of 3-[(4-fluorophenyl)methyl]-2-[[1-[2-thienyl)-ethyl]-4-piperidinyl]methyl]-3H-imidazo[4,5-b]pyridine dihydrochloride. monohydrate; mp. 210.8° C. (117).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.CC(O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: Cc1c(Br)cc2c(Cl)ncnc2c1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1c(Br)cc2c(Nc3ccc(C#N)cc3)ncnc2c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 6-bromo-4-chloro-7-methyl-8-nitroquinazoline (211 mg, 0.70 mmol) and 4-aminobenzonitrile (208 mg, 1.76 mmol) in toluene (25 mL) was refluxed overnight. i-PrOH (25 mL) was added and the mixture was refluxed for 5 h. After cooling to rt the precipitate was filtered and washed with i-PrOH to give 4-(6-bromo-7-methyl-8-nitroquinazolin-4-ylamino)benzonitrile (195 mg, 72%). MS (ESI, pos. ion) m/z: 384 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](I)=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26]/[CH:27]=[CH:28]/B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5](/[CH:28]=[CH:27]/[CH2:26][O:25][CH3:24])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2I)CC1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC/C=C/c1cnc(Cl)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 65.4 %

Procedure:
A solution of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)piperidine-1-carboxylate (Synthesis 170-B) (0.100 g, 0.22 mmol), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.044 g, 0.22 mmol), sodium carbonate (0.5 M, 0.66 mL) and tetrakis(triphenylphosphine) palladium(0) (0.013 g, 0.01 mmol) in acetonitrile (2.00 mL) was heated under microwave irradiation for 20 min at 100° C. The solvent was removed in vacuo and the crude product was purified by silica column chromatography, eluting with ethyl acetate and hexane (1/1). to give the title compound as a colourless oil (0.057 g, 65%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([CH2:16][C:17]23[O:28][C:18]2([C:24](OC)=[O:25])[C:19]([CH3:23])([CH3:22])[CH2:20][CH2:21]3)=[CH:14][CH:13]=1.C(OCC)C>COCCOC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2([OH:28])[CH2:24][OH:25])=[CH:29][CH:30]=1
Reactant: COC(=O)C12OC1(Cc1ccc(Cl)cc1)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: COCCOC
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)CO
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
2.7 g (71 mmol) lithium aluminium hydride were added to a suspension of 2.7 g (24 mmol) aluminium chloride partially dissolved in 120 ml 1,2-dimethoxyethane, the addition of lithium aluminium hydride causing a rise in temperature to 50° C. The resulting slurry was incubated at 50° C. for 30 minutes. A solution of 6.8 g (23 mmol) 1-(4-chlorobenzyl)-1,2-epoxy-3,3-dimethyl-2-methoxycarbonylcyclopentane prepared as described in Example 1 (g) in 30 ml 1,2-dimethoxyethane was then added over a period of 30 minutes whilst maintaining the temperature of the reaction mixture at 50°-55° C. After 1 hour, thin layer chromatography indicated that the reaction was complete and the excess lithium aluminium hydride was therefore destroyed by adding 10 ml saturated ammonium chloride solution followed by 10 ml water. This produced a sludgy solid which filtered only slowly. After filtration, the solid was dissolved in 2N hydrochloric acid and extracted twice with diethyl ether. The extracts were combined with the filtrate and flashed to give 5.9 g crude product. Trituration with cold 60/80 petroleum and a little diethyl ether gave 5.45 g 1-(4 -chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-hydroxymethylcyclopentane as a white solid, m.pt. 103°-104° C. Yield: 82%.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(Cl)=[S:12]>Cl>[N:1]([C:2]1[C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc2ccoc12
Agent: Cl
Product: S=C=Nc1cccc2ccoc12

Procedure:
7-Amino-benzo[b]furan is reacted with thiophosgene in 3 N hydrochloric acid at room temperature over 1 hour to give 7-isothiocyanatobenzo[b]furan. (M.Pt. 45°-46° from petroleum ether.) Reaction of this isothiocyanate with ethanolamine in ether gives N-benzo[b]furan-7-yl-N'-2-hydroxyethylthiourea (m.pt. 138°-139° from methanol) which is used further in the crude state.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[BH4-].[Na+].Cl.O>C(O)C.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(C)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
To a solution of 1-(4-methyl-3-nitrophenyl)ethan-1-one (2.00 g) in ethanol/tetrahydrofuran (15 mL/7.5 mL) was added sodium borohydride (211 mg), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added 0.5 mol/L hydrochloric acid and water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (1.96 g). 1H-NMR (CDCl3) δ ppm: 1.52 (3H, d, J=6.5 Hz), 1.84-1.95 (1H, m), 2.59 (3H, s), 4.91-5.02 (1H, m), 7.32 (1H, d, J=7.9 Hz), 7.52 (1H, dd, J=1.8, 7.9 Hz), 7.99 (1H, d, J=1.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[C:3]=1[C:4]#[N:5].[NH2:15][S:16](Cl)(=[O:18])=[O:17]>CC(N(C)C)=O.CCOC(C)=O>[S:16]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[C:3]=1[C:4]#[N:5])(=[O:18])(=[O:17])[NH2:15]
Reactant: COC/C=C/c1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC/C=C/c1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (E)-2-amino-6-(3-methoxyprop-1-enyl)benzonitrile (Example 97b) (188 mg, 1.0 mmol) in DMA was added NH2SO2Cl (347 mg, 3.0 mmol) at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature for 6 hrs, diluted with EtOAc, washed with brine (5×), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give (E)-2-sulfamoylamino-6-(3-methoxyprop-1-enyl)benzonitrile as a pale-yellow solid, which was used in the next step without further purification.
Reaction SMILES: NN1CCCC1.Cl[C:8]1[N:9]=[C:10]([N:18]([CH3:20])[CH3:19])[C:11]2[S:16][C:15]([CH3:17])=[CH:14][C:12]=2[N:13]=1.[NH2:21][C@H:22]1[C@H:26]([OH:27])[CH2:25][N:24]([C:28](=[O:41])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:23]1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:19][N:18]([CH3:20])[C:10]1[C:11]2[S:16][C:15]([CH3:17])=[CH:14][C:12]=2[N:13]=[C:8]([NH:21][C@H:22]2[C@H:26]([OH:27])[CH2:25][N:24]([C:28](=[O:41])[CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=3)[CH2:23]2)[N:9]=1
Reactant: N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O
Reactant: Cc1cc2nc(Cl)nc(N(C)C)c2s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: NN1CCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2nc(N[C@@H]3CN(C(=O)Cc4ccc(OC(F)(F)F)cc4)C[C@H]3O)nc(N(C)C)c2s1
Temperature: 60 °C
Reaction time: 5 h
Yield: 29.7 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.15 g) in ethanol (5 mL) were added 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (0.25 g) and triethylamine (0.12 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine and then dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure and crystallized with diethyl ether to obtain 2-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amine (0.16 g). (2) To a mixture of 2-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amine (0.150 g), Pd2(dba)3 (0.033 g), (±)-BINAP (0.067 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.26 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.21 g) under nitrogen atmosphere, and the mixture was stirred at 60° C. for 5 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain light yellow amorphous 1-((3R,4R)-3-(4-dimethylamino-6-methylthieno[3,2-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.097 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:22][C:21]([O:33][CH3:34])=[CH:20][CH:19]=2)(C)(C)C>ClCCl>[CH2:26]([O:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:33][CH3:34])[N:22]=2)[N:17]=[CH:16][C:15]=1[NH2:14])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2ncc(NC(=O)OC(C)(C)C)c(OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(N)c(OCc3ccccc3)c2n1
Temperature: 0 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
Trifluoroacetic acid (10.0 mL, 131.2 mmol, 20.0 eq) is added at 0° C. to a stirred solution of (4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yl)-carbamic acid tert-butyl ester (2.50 g, 6.55 mmol, 1.0 eq) in dichloromethane (50 mL). After 20 hours stirring at 0° C., the reaction mixture is extracted with dichloromethane (3×200 mL) and water (200 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ylamine as a light yellow solid (1.70 g, 92% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:10]=1)=[O:4].C(O)(=O)C.CO>[Pd].O1CCCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:22])[S:7][CH:8]=2)=[CH:14][CH:15]=1
Reactant: CC(C)C(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
A mixture of 2-methyl-N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}propanamide (333 mg), palladium on carbon (33 mg), acetic acid (1 ml), methanol (2 ml) and tetrahydrofuran (2 ml) was stirred under hydrogen atmosphere (4 atm) at ambient temperature for 5 hours. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5% methanol/ethyl acetate as an eluent. The solid residue was collected and washed with diisopropyl ether to give N-{4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}-2-methylpropanamide (260 mg).
Reaction SMILES: [F:1]/[C:2](=[C:8](/[CH3:22])\[CH:9]=[CH:10]\[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([CH3:20])[C:12]=1[Cl:21])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>>[F:1]/[C:2](/[C:8](/[CH3:22])=[CH:9]/[CH2:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([CH3:20])[C:12]=1[Cl:21])=[CH:3]\[OH:4]
Reactant: CCOC(=O)/C(F)=C(C)/C=C/c1c(Cl)cc(OC)c(C)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Product: COc1cc(Cl)c(C/C=C(C)/C(F)=C/O)c(Cl)c1C
Temperature: -45 °C
Yield: 80 %

Procedure:
A solution of 8.5 g. (24.5 mmol) of ethyl 2Z,4E-2-fluoro-3-methyl-5-(2,6-dichloro-3-methyl-4-methoxyphenyl)pentadienoate was stirred under argon and cooled to -45° C. Diisobutylaluminum hydride (DIBAH) was added slowly until three equivalents had been added and no starting material remained by tlc. Saturated aqueous sodium sulfate (5 ml.) was added at -10° C. and the mixture was allowed to warm to 30° C. for completion of hydrolysis. The mixture was filtered through Celite and the filtrate was evaporated. The residue was chromatographed on silica to give 6.0 g. (80% yield) of 2Z,4E-2-fluoro-3-methyl-5-(2,6-dichloro-3-methyl-4-methoxyphenyl)pentadien-1-ol.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:33]=[CH:32][C:8]2[O:9][C:10]3[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=3[CH2:12][N:13]([C:14](=[O:27])[CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[C:7]=2[CH:6]=1>C(O)C>[NH2:16][CH2:15][C:14]([N:13]1[CH2:12][C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[O:9][C:8]2[CH:32]=[CH:33][C:5]([Cl:4])=[CH:6][C:7]1=2)=[O:27]
Reactant: O=C1c2ccccc2C(=O)N1CC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
Hydrazine monohydrate (1.25 mi) and 8-chloro-10,11-dihydro-10[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)acetyl]-dibenz[b,f][1,4]-oxazepine (5.00 grams) were refluxed in absolute ethanol (125 mi) for 4 hours. The resulting mixture was filtered hot, and the collected solid was rinsed twice with ethanol, and then with hot methylene chloride. The filtrate and rinses were combined, evaporated i-n vacuo, and purified by flash chromatography through silica gel 60 (300 mi) using 95:5:0.5 chloroform:methanol:ammonium hydroxide. Trituration of the purified product with ethyl ether/hexane yielded the title compound as a white solid. Yield: 2.91 grams (84%). Mp: 108°-1090° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[N:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.Cl[Sn]Cl>Cl.CO>[N:9]1[C:10]2[C:5](=[C:4]([NH2:1])[CH:13]=[CH:12][CH:11]=2)[N:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccc2nccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1cccc2nccnc12
Yield: 98.9 %

Procedure:
In a similar fashion using route 2 general procedure 4, 5-nitroquinoxaline 481 (660 mg, 3.76 mmol), SnCl2 (2.14 g, 11.3 mmol), 6N HCl (6 drops) and MeOH (15 ml) for 3 h at 70° C. gave the title compound (540 mg, 98%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[CH:9]=[C:8]([OH:11])[CH:7]=[CH:6][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCCc1ccc(O)cc1Br
Temperature: 40 °C
Reaction time: 4 h

Procedure:
22.5 g (0.15 mol) of commercially available p-n-butylphenol was dissolved in 100 ml glacial acetic acid and was slowly heated to 40° C. 24.5 g (0.153 mol) of bromine was added and the solution was stirred for four hours at 60° C. The glacial acetic acid in the reaction solution was removed by distillation and 31.7 g of 3-bromo-4-n-butylphenol was obtained from the residue by vacuum distillation (85° C./1 mmHg). The yield of 3-bromo-4-n-butylphenol was calculated to be 92.1%.