Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].Br[CH:4]1[CH:9]2[CH:10]([OH:15])[CH:11]([OH:14])[CH:12]([OH:13])[C:5]1([CH2:17][OH:18])[O:6][C:7](=[O:16])[NH:8]2.C(O)(=O)C>O>[OH:15][CH:10]1[CH:11]([OH:14])[CH:12]([OH:13])[C:5]2([CH2:17][OH:18])[CH2:4][CH:9]1[NH:8][C:7](=[O:16])[O:6]2
Reactant: O=C1NC2C(O)C(O)C(O)C(CO)(O1)C2Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC2CC(CO)(O1)C(O)C(O)C2O
Yield: 87 %

Procedure:
Sodium borohydride (55 g) is added by portions to a solution of 9-bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (100 g) in water (1.3 l) at 25°-30° C. with stirring. After stirring for 2 hours at the same temperature, the reaction mixture is adjusted to pH 6-7 with acetic acid and concentrated to about 800 ml under reduced pressure. The concentrate is chromatographed on a column of activated carbon (4.8 l), and the column is washed with water (5 l) and eluted with 50% aqueous methanol. The eluate is concentrated under reduced pressure. Methanol (350 ml) is added to the residue and refluxed for 10-20 minutes to remove a methanol soluble by-product. The mixture is allowed to stand in a refrigerator overnight, and the resulting crystals are collected by filtration, followed by washing with cold methanol and drying in a desiccator under reduced pressure to give 6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (64 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.N>Br>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: Br
Agent: N
Solvent: O
Product: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 95.6 %

Procedure:
The product from step (i) (1.5 g) in concentrated hydrobromic acid (30 ml) was heated under argon at 130°-135° C. for 21/2 hours. The solution was cooled, poured into water (150 ml) and basified with aqueous ammonia. The precipitate was filtered, washed with water and dried to give 4-[4(4-pyridyl)piperazin-1-yl]phenol (1.36 g) as a solid: m.p. 310°-312° C.; NMR(d6DMSO) δ8.2(2H,d); 6.8(4H,m); 6.66(2H,d); 3.45(4H,m); 3.08(4H,m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[I-].[K+]>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCCCCCCCCCCCO
Temperature: 80 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
25.9 g (170 mmol) of 4-hydroxy-3-methoxybenzaldehyde and 38.9 g (155 mmol) of 11-bromoundecan-1-ol are dissolved in 200 mL of N,N-dimethylformamide. 23.57 g (170 mmol) of potassium carbonate and 2.47 g (15 mmol) of potassium iodide are added and the suspension is heated to 80° C. After 12 h, the reaction mixture is cooled to room temperature and poured to icy water. The precipitate is filtered off, digested in 500 mL of water and the mixture was neutralized with hydrochloric acid 37%. The precipitate is filtered off, washed with water and dried overnight at 40° C. 48.5 g of 4-[(11-hydroxyundecyl)oxy]-3-methoxybenzaldehyde are obtained as a slightly pink solid (97% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [CH2:1]([N:8]([CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][C:22]=2[CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42].N1C=CN=C1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([N:8]([CH2:9][C@H:10]([O:19][Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:30][C:22]=2[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H](COc1ccccc1)CN(Cc1ccccc1)C1CCCc2ccc(OCc3ccccc3)cc2C1
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C1CCCc2ccc(OCc3ccccc3)cc2C1

Procedure:
Under nitrogen, a solution of (2S)-1-[N-benzyl-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (20 g), chlorotriethylsilane (7.4 ml), imidazole (3.2 g) and 4-dimethylaminopyridine (0.48 g) in N,N-dimethylformamide (200 ml) was stirred at room temperature for 12 hours. The resulting mixture was poured into water, and extracted with ethyl acetate-hexane (1:1). The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give N-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)-propyl]amine (25 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Reaction time: 8 h
Yield: 35.3 %

Procedure:
Methyl 2-[(4-{2-[benzyl(hexyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (70 mg, 0.148 mmol) in THF (2 ml) was cooled in an ice-bath. Lithium hydroxide (7.08 mg, 0.296 mmol) in water (1 ml) was dropped in. The cooling-bath was then removed and the mixture was stirred overnight. HPLC showed that the reaction was not complete. More lithium hydroxide (0.2M, 0.5 ml) was added. The reaction mixture was stirred for 4 days more. It was then evaporated in vacuum to remove THF. The residue was acidified with 1% hydrochloric acid, pH=3-4, and extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (1:99, and then 2:98) as eluant gave 24 mg the desired product, yield 35%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4](O)[N:3]=1.O=P(Cl)(Cl)[Cl:13].N(C1C=CC=CC=1)(CC)CC>>[Cl:13][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1nc(O)nc(C)c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc(Cl)nc(C)c1C
Yield: 101.9 %

Procedure:
To 4,5,6-trimethylpyrimidin-2-ol (3.69 g, 26.7 mmol) was added POCl3 (21.7 mL, 26.7 mmol) followed by Et2NPh (2.17 mL, 13.6 mmol) dropwise. The mixture was heated at reflux for 48 h and then added to ice dropwise. The aqueous layer was extracted with EtOAc (2×). Extraction was difficult due to a large amount of precipitate. The aqueous layer pH was adjusted to pH 4-5 with 28% NH4OH and was filtered through Celite®. The aqueous layer was then extracted with DCM and the combined organic extracts dried over Na2SO4, filtered and concentrated in vacuo to a yellow solid. Chromatography (FCC) (0 to 30% EtOAc/Hex) afforded 2-chloro-4,5,6-trimethylpyrimidine (4.26 g, 100%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1>CO.[Pd]>[F:18][C:2]([F:1])([F:19])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ccc(C(F)(F)F)nc1

Procedure:
The product of Step C (2.2 g, 8.1 mmol) in 40 mL methanol and 5% palladium on carbon (0.25 g) was stirred under hydrogen atmosphere (balloon) for 1 h. The reaction mixture was filtered through filter aid and the solvent removed under vacuum to afford the product as a solid, MS: m/z 276 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][S:13][C:14](=[N:17][C:18]#[N:19])SC>C(O)C>[C:18]([NH:17][C:14](=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])[S:13][CH3:12])#[N:19]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NCCSCc1[nH]cnc1C)NC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
(i) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (23.4 g.) in ethanol was added slowly to a solution of dimethylcyanodithioimidocarbonate (20.0 g.) in ethanol, with stirring at room temperature. The mixture was set aside overnight at room temperature. Filtration afforded N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.0 g.) m.p. 148°-150°. The filtrate was concentrated under reduced pressure and the mixture was triturated with cold water and the solid obtained, filtered off and recrystallised twice from isopropyl alcohol/ether to yield further product (27 g.), m.p. 148°-150°.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Oc1cccc(F)c1-n1cccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc2c1-n1cccc1C1(CCNCC1)O2
Reaction time: 12 h
Yield: 79.3 %

Procedure:
3-Fluoro-2-(1H-pyrrol-1-yl)phenol (2.7 g, 16.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.3 g, 16.6 mmol) were dissolved in dry dichloromethane (53.6 mL). TFA (2.3 mL, 30.3 mmol) was added over 15 min and stirring was continued for 12 hours. Additional TFA (2.3 mL, 30.3 mmol) was added at 25° C. The reaction mixture was concentrated under vacuum and the residue diluted with dichloromethane (350 mL) then washed with 1M NaOH (2×50 ml), dried, filtered and evaporated to dryness. The resulting material was purified by silica gel chromatography eluting with 0.5-40% MeOH in dichloromethane to yield 9-fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (3.4 g, 86%). ESI-MS m/z calc. 258.1. found 259.1 (M+1)+; Retention time 0.90 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of 4-Bromo-2-nitroaniline (435 mg, 2 mmol) and benzaldehyde (0.204 ml, 2 mmol,) in 4 ml dry dichloromethane at room temperature, was added sodium triacetoxyborohydride (424 mg, 2 mmol). Then acetic acid (120 μl, 2 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. The solvent was evaporated and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude material was purified by flash chromatography to yield 276 mg (0.9 mmol, 45%) of benzyl-(4-bromo-2-nitrophenyl)-amine.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH2:13]1COCC1.C[Mg]Br.C1COCC1.O>CCOC(C)=O>[OH:1][C:2]1([CH3:13])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: C[Mg]Br
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
tert-Butyl 3-oxoazetidine-1-carboxylate (1 g) and THF (20 ml), which had been cooled to 0° C., were mixed, and a 1.12 M methylmagnesium bromide/THF solution (10 ml) was added thereto, followed by stirring at the same temperature for 1 hour. Water and EtOAc were added to the reaction mixture, the organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (1.0 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:30]2
Reactant: Clc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)c(NCCO)c2c1=O
Yield: 35.1 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8- trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 101 mg of 4-chloroisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 100 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.CN.CC(O)=O.[C:19]([BH3-])#[N:20].[Na+]>CO>[CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][NH:20][CH3:19]
Reactant: Cc1c(C=O)sc2ccccc12
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1sc2ccccc2c1C
Temperature: 25 °C
Yield: 56 %

Procedure:
To a stirred solution of 3-methylbenzo[b]thiophene-2-carboxaldehyde (0.5 g, 2.8 mmole) in methanol (15 mL) was added 2.0 M methylamine in methanol (6 mL, 12 mmole) and HOAc (0.32 mL, 5.7 mmole). The reaction was stirred at RT for hr, then sodium cyanoborohydride (0.2 g, 3 mmole) was added in one portion. After stirring for an additional 16 hr the reaction was concentrated to dryness. The residue was taken up in Et2O and washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated under vacuum. Purification by flash chromatography on silica gel (95:5 CHCl3/methanol containing 5% NH4OH) gave the title compound (0.30 g, 56%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.34 (t, 1H), 7.28 (t, 1H), 3.99 (s, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 1.77 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:29]=[CH2:28]
Reactant: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2c(Nc3ccc(Cl)cc3)ncnc2cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol (0.61 g, 2.02 mmol) (from Example 16, Step B, supra) in acetone (50 mL) was added K2CO3 (0.84 g, 6.06 mmol), and allyl bromide (0.52 mL, 6.06 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.01) as eluent to give the desired (6-allyloxy-7-methoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine as a white solid. (Yield 0.5 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.[H-].[Na+].[CH3:12]I.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:12])[CH:7]=1
Reactant: CI
Reactant: OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-bromo-5-hydroxymethylpyridine (379 mg, 2.0 mmol) in dry tetrahydrofuran (10 mL) was treated at ambient temperature with sodium hydride (160 mg, 4.0 mmol, 60% dispersion in mineral oil). After stirring 5 min at ambient temperature, the opaque, yellow mixture was treated with methyl iodide (342 mg, 2.4 mmol). After stirring 2 h at ambient temperature, the mixture was added to cold water (30 mL) and extracted with diethyl ether (3×20 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to an orange oil (429 mg). Purification by column chromatography on silica gel, eluting with 15% (v/v) ethyl acetate in hexane afforded 266 mg (65.3%) of 3-bromo-5-methoxymethylpyridine as a colorless oil.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]N)=[CH:11][C:10]=1[N+:17]([O-:19])=O)([C:3]([O:5]CC)=O)=[O:2].[CH3:20][N:21](C)C=O>>[C:20]([CH2:13][C:12]1[CH:11]=[C:10]2[C:9]([NH:8][C:1](=[O:2])[C:3](=[O:5])[N:17]2[OH:19])=[CH:16][CH:15]=1)#[N:21]
Reactant: CCOC(=O)C(=O)Nc1ccc(CN)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: N#CCc1ccc2[nH]c(=O)c(=O)n(O)c2c1
Yield: 82 %

Procedure:
A solution of 1.0 g (3.6 mmol) 4-ethoxalylamino-3-nitrobenzylamine in 30 ml dimethylformamide was hydrogenated at atm. pressure by using 100 mg 5% Pt-c as a catalyst. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was stirred with water and the precipitate was filtered off. The product was washed with water and 5 ml ethanol to give 0.64 g (82%) of 7-cyanomethyl-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 12,3 (1H, broad s), 7.6-7.3 (3H, m), 4.2 (2H, s). IR (KBr): 2250 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C([Sn](CCCC)(CCCC)[C:17]1[O:18][C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:21]=1)CCC>O1CCOCC1>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:19]1[O:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])=[CH:21][CH:20]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([Sn](CCCC)(CCCC)CCCC)o1
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1-c1ccc(-c2ccc([N+](=O)[O-])cc2C)o1
Yield: 84.8 %

Procedure:
To a solution of 2-bromo-5-nitrotoluene (4.32 g, 20 mmol) and tetrakis (triphenylphospine) palladium (0) (0.40 g) in anhydrous 1,4-dioxane (50 ml) was added 2,5-bis (tri-n-butylstannyl) furan (6.46 g, 10 mmol) and the mixture was heated overnight under nitrogen at 95–100° C. The resulting orange suspension was diluted with hexanes (15 ml), cooled to room-temperature, and filtered to give, after rinsing with hexanes, an orange solid (3.10 g), mp 241–243° C. The product was recrystallized from DMF (100 ml) to give a bright orange fluffy solid (2.87 g, 85%), mp 242–243° C. 1H NMR (DMSO-d6): 2.69 (s, 6H), 7.31 (s, 2H), 8.12 (m, 4H), 8.23 (s, 2H). Anal. Calcd. for C18H14N2O5 (338.31): C, H, N.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[Cl:20])=[O:28]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CNC(=O)c3[nH]cnc3Cl)c2Cl)c1
Yield: 75.8 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(aminomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (40 mg, 0.129 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (35.6 mg, 0.129 mmol), EDC (29.6 mg, 0.154 mmol) and HOBT (29.5 mg, 0.193 mmol) in DMF (3.0 ml) to give the title compound as a white solid (43 mg, 76%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.62 (1H, s) 7.40 (1H, dd, J=8.5, 5.4 Hz) 7.35 (2H, br. s.) 7.12-7.22 (2H, m) 7.00 (1H, s) 4.75 (2H, d). LCMS: m/z 439 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:34]1[C:46]2[CH:45]([CH2:47][O:48][C:49]([NH:51][C@H:52]([C:58](O)=[O:59])[CH2:53][CH2:54][C:55](=[O:57])[NH2:56])=[O:50])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1.[C:61]([O:65][C:66](=[O:82])[NH:67][CH2:68][CH2:69][CH2:70][C@H:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:72][NH2:73])([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C>[CH:43]1[C:44]2[CH:45]([CH2:47][O:48][C:49](=[O:50])[NH:51][C@H:52]([C:58]([NH:73][CH2:72][C@@H:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:70][CH2:69][CH2:68][NH:67][C:66]([O:65][C:61]([CH3:63])([CH3:64])[CH3:62])=[O:82])=[O:59])[CH2:53][CH2:54][C:55]([NH2:56])=[O:57])[C:46]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: NC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCC(N)=O)NC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
129 mg (0.34 mmol) of HATU and 133 mg (0.95 mmol) of N,N-diisopropylethylamine are added to a solution of 100 mg (0.27 mmol) of N2-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-glutamine and 112 mg (0.35 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 5 ml of anhydrous DMF at 0° C. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is stirred with water, collected by filtration and dried under high vacuum.
Reaction SMILES: C[S:2][C:3](=S)[O:4][CH:5]([CH3:7])[CH3:6].[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)(=[O:11])[CH3:10].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9](=[O:11])[CH2:10][C:3](=[S:2])[O:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(=O)c1ccco1
Reactant: CSC(=S)OC(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)OC(=S)CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of isopropyl (methylsulfanyl)methanethioate (7.0 g, 46.7 mmol), 2-acetyl furan (5.14 g, 46.7 mmol), potassium t-butoxide (10.5 g, 93.5 mmol) and t-butanol (35 mL) was stirred overnight at room temperature. Ice was added to the reaction solution, followed by acidifying with 5 N hydrochloric acid. The solid was collected by filtration and washed with water, to give the title compound (3.7 g, 37%).