Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH2:15][NH2:16].[BH4-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(F)c1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CC(C)NCC(O)c2cccc(F)c2)cc1

Procedure:
1-(4-Methoxyphenyl)propan-2-one (2.25 g) and 2-hydroxy-2-(3-fluorophenyl)ethanamine (2.13 g) were condensed ahd subsequently reduced with sodium borohydride (2.75 g) by an analogous procedure to that described in Example 1. The crude product was recrystallised from diethyl ether-hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-fluorophenyl)ethanamine, mp 85°-9° C., as a 37:63 mixture of diastereoisomers.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH2:23]1[CH2:26][CH2:25][CH:24]1C=O.C(O)=O.C(N(CC)CC)C>CO.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[CH:23]1([CH2:1][N:2]2[CH2:3][CH2:4][C@@:5]34[C:15]5[C:14]6[CH2:13][C@@H:12]2[C@:11]3([OH:22])[CH2:10][CH2:9][C:7](=[O:8])[C@@H:6]4[O:21][C:16]=5[C:17]([OH:20])=[CH:18][CH:19]=6)[CH2:26][CH2:25][CH2:24]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: O=CC1CCC1
Agent: Cl[Ru]Cl
Solvent: O=CO
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCN(CC)CC
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)[C@H]1O5
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of Noroxymorphone (8.8 g, 30.6 mmol) in methanol (250 mL) was degassed for 20 minutes. 2-cyclobutanecarbaldehyde (7.7 g, 91.5 mmol) was added and the mixture heated at reflux for 1 hour. The reaction mixture was cooled to ambient temperature. In a separate flask formic acid (14.0 g, 306 mmol) was added slowly to a solution of triethylamine (12.4 g, 123 mmol) in methanol (40 mL). The formic acid solution was stirred for 5 minutes before being added to the solution containing Noroxymorphone along with dichloro(p-cymene)ruthenium(II) dimer (53 mg). The reaction was heated at reflux for a further 2.5 hours. The reaction was concentrated under reduced pressure then partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase was extracted with further ethyl acetate then the organic layers combined and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave (4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (10.2 g, 94% yield); LC/MS (M+H)+=356.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.[CH3:14][N:15](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[F:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:12][CH3:13])[C:5]=1[N+:9]([O-:11])=[O:10])[C:14]#[N:15]
Reactant: COc1cc(Br)cc(F)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Yield: 84 %

Procedure:
Into a microwave vial was added 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (1.75 g, 7.00 mmol), Pd(PPh3)4 (1.132 g, 0.9798 mmol), and zinc cyanide (0.8222 g, 7.002 mmol). The vial was sealed, and then DMF (28 mL) was added. The vial was evacuated and purged with N2 gas (3 times). The reaction mixture was irradiated on the microwave for 3-5 minutes at 150° C. The reaction mixture was quenched with water (30 mL) and then extracted with EtOAc (60 mL). The organic layer was washed with water (30 mL), brine (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The crude material was purified by silica gel chromatography on an ISCO combi-flash Rf system using Heptane/EtOAc (100:0→55:45) as eluent to yield the desired product as a light yellow solid 1.15 g (84% yield). 1H NMR (CDCl3, 400 MHz): δ=4.01 (s, 3H), 7.14 (t, J=1.52 Hz, 1H), 7.19 (dd, J=8.21, 1.39 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=3)=[N:9][CH:10]=2)[CH2:2]1.C=O.[BH3-][C:24]#N.[Na+].C(OCC)C>CO.[Cl-].[Zn+2].[Cl-].O>[Br:18][C:16]1[CH:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH:3]3[CH2:4][N:1]([CH3:24])[CH2:2]3)=[CH:10][N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 239b (469 mg, 1.4 mmol), 37% aqueous formaldehyde (4.0 g, 50 mmol), NaBH3CN (261 mg, 4.2 mmol), and 1M zinc chloride in ethoxyethane (4 mL, 4.2 mmol) in methanol (40 mL) was stirred at room temperature for 2 hours. The mixture was added to water (20 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 10:1 methylene chloride/methanol to afford 239c as a yellow solid (300 mg, 83%). MS-ESI: [M+H]+ 349.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@:9]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10])=[O:4].Cl>CC#N>[Cl:17][C:13]1[CH:12]=[C:11]([C@@:9]([OH:10])([C@@H:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-tert-butyl 3-((S)-4-(methoxycarbonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.0322 g, 0.073 mmol), CH3CN (30 mL) and 2 N aq HCl (25 mL) was vigorously stirred at rt for 24 h. The solvents were removed in vacuo to give the HCl salt of methyl (S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate, which was used without further purification. LC-MS (3 min) tR=0.98 min, m/z 343, 341 (M+H+), 323.
Reaction SMILES: [CH2:1]=O.Cl.[CH2:4]([O:11][NH2:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[CH2:4]([O:11][N:12]=[CH2:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=NOCc1ccccc1
Reaction time: 2 h

Procedure:
37% Formaldehyde (11.7 mL) was added to a slurry of benzyloxyamine hydrochloride (25.0 g, 0.156 mole) in 50 mL H2O. NaOH (6.3 g) in 25 mL H2O was then added over 20 minutes. The temperature rose to 40°. After stirring 2 hours, the reaction mixture was extracted 1×100 mL and 2×25 mL of ether. The ether extracts were combined, washed 2×50 mL saturated NaHCO3 and then 2×50 mL brine, dried and evaporated to yield title product as an oil, 20.0 g, b.p. 195.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:34]=[CH:33][S:32][C:18]=3[N:19]=[C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:34]=[CH:33][S:32][C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2nc(Nc3cc(OC)cc(N4CCC[C@@H]4C)c3)c3ncsc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Temperature: 30 °C
Yield: 43.3 %

Procedure:
The mixture of (S)-methyl 4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (121 mg, 0.25 mmol) and NaOH (102 mg, 2.54 mmol) in dioxane (20 mL) and H2O (10 mL) was heated to 30° C. for 2 h. The reaction mixture was concentrated and the aqueous residue was adjusted to pH˜4 by the addition of conc. HCl. The solution was extracted with ethyl acetate (10 mL×3), then combined organics dried over Na2SO4 and concentrated to afford (S)-4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (50 mg, crude) as yellow solid which was used to next step without purification. LC-MS: 462 [M+H]+, tR=1.699 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C1CCN2C(=NCCC2)CC1.[CH:34](=[O:39])/[CH:35]=[CH:36]/[CH2:37][CH3:38].O>C(#N)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:36]([CH2:37][CH3:38])[CH2:35][CH:34]=[O:39])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC/C=C/C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 1 h

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (100 mg, 0.0003 mol) in ACN (2 mL, 0.04 mol) and DBU (50 μL, 0.0003 mol), the (2E)-pent-2-enal (4.0E1 mg, 0.00048 mol) in 1 mL ACN was added drop wise. The reaction was stirred for 1 h, and then water was added and the resulting mixture extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the crude as the hydrated product form. LC/MS (M+H)+: m/z=400.
Reaction SMILES: O[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][S:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH2:22])=[C:20]([CH3:27])[CH:19]=1.Cl.N1C=CC=CC=1>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH:22][C:13]2[S:14][C:8]3[C:9]([N:12]=2)=[CH:10][C:11]2[CH:2]=[C:3]([C:15]#[N:16])[CH:4]=[N:5][C:6]=2[CH:7]=3)=[C:20]([CH3:27])[CH:19]=1
Reactant: N#Cc1cnc2cc3scnc3cc2c1O
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2nc3cc4cc(C#N)cnc4cc3s2)c(C)cc1Cl
Yield: 15.5 %

Procedure:
To a mixture of 100 mg (0.44 mmol) of 8-hydroxy[1,3]thiazolo[4,5-g]quinoline-7-carbonitrile in 5 mL of phosphoryl chloride is added five drops of N,N-dimethylformamide. The mixture is heated at reflux temperature for 30 minutes and then concentrated in vacuo. To the residue at 0° C. is added 50 mL of water. The solids are collected, washed with water, and dried in vacuo. To a mixture of this compound in 2 mL of 2-ethoxyethanol are added 76 mg (0.44 mmol) of 4-chloro-5-methoxy-2-methylaniline and 20 mg of pyridine hydrochloride. The mixture is refluxed for one hour and concentrated. The residue is chromatographed by silica gel chromatography, eluting with 9:1 methylene chloride/methanol to yield 26 mg (16%) of product as a dark oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:21]=[C:20]([CH3:22])[C:12]([O:13][CH2:14][C:15]([O:17]CC)=O)=[C:11]([CH3:23])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:15](=[O:17])[CH2:14][O:13][C:12]1[C:11]([CH3:23])=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:24])([F:25])[F:1])[C:4]([F:6])([F:5])[F:7])=[CH:21][C:20]=1[CH3:22])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)COc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(=O)NCc1ccccc1
Temperature: 110 °C

Procedure:
Combine ethyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetate (7.0 g=19 mmol) and benzylamine (12.0 g=0.11 mmol). Heat 4 hours at 110° C., allow to cool, and partition between 1.0 N HCl and ether. Dry and concentrate the ether. Recrystallize from ether-hexane and obtain, as a white solid, m.p. 142°-144° C., N-benzyl-2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetamide.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[OH:24])[CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]1)C1C=CC=CC=1>O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[C@H:15]1[C@H:11]([CH2:10][CH2:9][OH:8])[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14]1
Reactant: COc1ccc([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CCOCc2ccccc2)c(O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CCO)c(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product from Example 280C (450 mg, 1.05 mmol) in 20 mL of tetrahydrofuran was added wet 20% Pd(OH)2 in a 250 mL stainless steel pressure bottle. The vessel was capped and stirred for three hours under hydrogen (30 psi) at room temperature. The reaction was filtered through a nylon membrane and concentrated. The crude product was chromatographed on a silica gel column eluting with 3:1 ethyl acetate/hexane to afford the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24-1.59 (m, 11H) 2.35 (d, J=7.12 Hz, 1H) 2.86-2.98 (m, 1H) 3.06-3.18 (m, 2H) 3.48-3.71 (m, 5H) 3.96-4.06 (m, 2H) 4.36 (s, 1H) 6.32-6.41 (m, 2H) 7.03 (d, J=8.48 Hz, 1H) 9.42 (s, 1H).
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH:11]([CH:13]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:14](OCC)=O)=[O:12]>CO>[N+:1]([NH:4][C:5]1[NH:7][C:11](=[O:12])[C:13]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[CH:14][N:6]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C=O)Cc1ccc(OC)nc1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1

Procedure:
Nitroguanidine (4.7 g) was added to a solution of sodium methoxide (prepared from 1.15 g sodium) in methanol (50 ml) and the mixture was heated under reflux for 45 minutes. Ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (10.7 g) was added and the mixture was heated under reflux for 24 hours and evaporated to dryness. The residue was dissolved in water and the solution was extracted with chloroform. The residual aqueous solution was adjusted to pH 5 with acetic acid, and the solid which precipitated was filtered off to give 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, m.p. 183.5°-186°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2.C([Li])CCC.[C:19](=[O:21])=[O:20].[OH-].[Na+]>O1CCCC1.CCCCCC>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:19]([OH:21])=[O:20])[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]2
Reactant: Cc1cn2c(n1)sc1ccccc12
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc2sc3ccccc3n2c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Methylimidazo[2,1-b]benzothiazole, 18.8 g, was suspended in 100 ml of dry tetrahydrofuran. Under cooling (at -78° C.), 100 ml of a solution of n-butyl lithium in n-hexane was dropwise added to the suspension over 15 minutes. After completion of the dropwise addition, the temperature was gradually raised and stirring was performed at 0° C. for 30 minutes. The mixture was again cooled to -78° C. After adding an excess of dry ice, the temperature was gradually raised and stirring was performed at 0° C. for 30 minutes. Under ice cooling, 200 ml of 2N sodium hydroxide solution was added to the reaction solution. After washing with ether, the aqueous phase was neutralized with acetic acid and the precipitated crystals were taken out by filtration. The crystals were stirred in 300 ml of chloroform for 30 minutes and 6.0 g of 2-methylimidazo[2,1-b]benzothiazole-3-carboxylic acid was obtained as the insoluble matter in chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1N.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].N(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[C:16]1[CH:17]=[C:12]([Cl:11])[C:13]([Cl:18])=[CH:14][CH:15]=1
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: Clc1ccccc1Cl
Agent: CC(C)(C)ON=O
Product: Clc1ccc(-c2cc(Cl)c(Cl)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2',4,4',5,5'-pentachlorobiphenyl was prepared according to the standard procedure of Cadogan [J. I. G. Cadogan, J. Chem. Soc. (London), 1962, 4257-58]. Thus, 2,4,5-trichloroaniline (20 g, 0.1 mol) was dissolved in 1,2-dichlorobenzene (125 mL, 1.1 mol). t-Butyl nitrite (28.2 mL, 1.1 mol) was introduce to the stirred solution in three portions over 10 min. After 15 min the evolution of gas had subsided, and the reaction mixture was heated to reflux behind a safety shield for 90 min, and then stirred at ambient temperature for 12 h. The excess 1,2-dichlorobenzene was removed in vacuo and the residue containing the product was purified by filtration through silica gel following the method of E. K. Yau and J. K. Coward, Aldrichimica Acta, 1988, 21(4), 106-107, to give after crystallization from ethanol the title product (3 g, 9.3%). Mass spectrum: m/z at 324 for C12H5Cl5.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16]([B:23]5[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]5)=[CH:17][CH:18]=4)[CH2:13]C[C:11]=3[CH:10]=2)[O:3]1.BrC1C=CC2C3C(=CC(Br)=CC=3)C(=[O:48])C=2C=1>>[CH3:29][C:26]1([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24][B:23]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[C:21](=[CH:22][C:9]([B:4]5[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:1])([CH3:32])[O:3]5)=[CH:10][CH:11]=4)[C:13](=[O:48])[C:14]=3[CH:15]=2)[O:27]1
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CC1(C)OB(c2ccc3c(c2)CCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C
Product: CC1(C)OB(c2ccc3c(c2)C(=O)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C

Procedure:
Followed the procedure used to prepare 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl]-[1,3,2]dioxaborolane, except that 2,7-dibromo-9-fluorenone was used instead of 2,7-dibromo-9,10-dihydro-phenanthrene.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.[H-].[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](F)=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N:3]2[CH2:4][CH2:5][CH:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]2=[O:1])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC1CCNC1=O
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(c2ccc(OCc3ccccc3)cc2[N+](=O)[O-])C1=O
Temperature: 0 °C
Yield: 26.5 %

Procedure:
Ethyl 2-(2-oxopyrrolidin-3-yl)acetate (1.77 g, 10.34 mmol) was dissolved in DMF (20 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.414 g, 10.34 mmol) was added. After stirring for several min, the reaction was allowed to warm to room temperature and stirred for 10 min. 4-(Benzyloxy)-1-fluoro-2-nitrobenzene (2.56 g, 10.34 mmol) was added and the mixture was stirred at room temperature for 21 h. The reaction was poured into water and acidified to pH 5 with 1.0 M HCL. The aqueous mixture was extracted three times with EtOAc and the combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (1.09 g). LCMS m/z=399.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (t, J=7.2 Hz, 3H), 1.97-2.01 (m, 1H), 2.46-2.59 (m, 2H), 2.95 (dd, J=12.9, 3.8 Hz, 1H), 2.96-3.06 (m, 1H), 3.69-3.76 (m, 1H), 3.79-3.88 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 5.13 (s, 2H), 6.90 (d, J=2.5 Hz, 1H), 6.94 (dd, J=9.0, 2.7 Hz, 1H), 7.37-7.42 (m, 5H), 8.04 (d, J=9.1 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:15][CH3:16])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([OH:10])=[O:9])C.[CH:17](NC)(C)C>>[CH:15]([N:4]([CH3:2])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([OH:10])=[O:9])([CH3:16])[CH3:17]
Reactant: CNC(C)C
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Agent: Cl
Product: Cc1cc(C(=O)O)cc(N(C)C(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-diethylamino-6-methyl-isonicotinic acid hydrochloride using isopropylmethylamine; LC-MS: tR=0.54 min; [M+H]+=209.09; 1H NMR δ 1.37 (d, J=6.3 Hz, 6H), 2.64 (s, 3H), 3.17 (s, 3H), 4.50-4.60 (m, 1H), 7.16 (s, 1H), 7.62 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH2:13][CH3:14].C([Li])CCC.CN(C)[CH:22]=[O:23]>O1CCCC1.[Cl-].[NH4+]>[CH2:13]([O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[O:23])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCOc1ccnc2ccc(Br)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccnc2ccc(C=O)cc12
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of 6-bromo-4-ethoxy-quinoline (0.53 g, 2.1 mmol) in THF (tetrahydrofuran) (21 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (0.92 mL, 2.3 mmol, 1.1 equiv.) at −70° C. During the addition, the temperature of the reaction mixture was raised slightly to −65° C. and it gave a very dark brown solution. The resulting colored solution was stirred for 30 min at this temperature. Then, a solution of dimethylformamide (0.324 mL, 4.2 mmol) in THF (2 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 15 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid which was purified by using a Biotage silica gel column chromatography to afford 0.370 g (88% yield) of 4-ethoxyquinoline-6-carbaldehyde as a white solid: EI-HRMS m/e calcd for C12H11NO2 (M+) 201.0790, found 201.0787
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][CH:19]=[N:20]4)=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].O[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1
Reactant: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1O
Reactant: OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCN1CCOCC1
Yield: 71.4 %

Procedure:
To a suspension of 7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (450 mg, 1.40 mmol), (prepared as described in Example 197), in DMF (50 ml) was added anhydrous potassium carbonate (773 mg, 5.60 mmol) and 4-(2-hydroxyethyl)morpholine (335 mg, 1.80 mmol), and the reaction heated under reflux for 2 hours. The DMF was evaporated in vacuo, and the residue partitioned between dichloromethane and 1N aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3×200 ml), dried (MgSO4) and concentrated in vacuo. The crude product was triturated with hexane/ether to afford a solid which was filtered and dried under suction to give 6-methoxy-7-(2-morpholinoethoxy)-4-(quinolin-7-yloxy)quinazoline (430 mg, 1.00 mmol, 71%) as a light brown solid.