Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].[Si](Cl)(C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C>CN(C=O)C.CC(C)=O>[CH2:14]([O:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH:1]=[O:13])=[CH:3][C:4]=1[O:5][CH3:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccccc1

Procedure:
4-Benzyloxy-3,5-dimethoxybenzaldehyde (13j) was prepared by the reaction of syringaldehyde with benzyl chloride in the presence of K2CO3 in boiling acetone. Similarly, reaction of t-butyldimethylsilyl chloride with syringaldehyde in DMF in the presence of N,N-diisopropylethylamine gave 4-(t-butyldimethylsilyl)-oxy-3,5-dimethoxybenzaldehyde (13k) (Scheme VII). Wittig reaction of phosphonium bromides 14a-b with benzaldehydes 13a-k in THF in the presence of sodium hydride followed by preparative thin-layer chromatographic separation of the crude products afforded the cis stilbenes 15a-k and trans stilbenex 16a-k (Scheme VIII). Reaction of compounds 15k and 16k with tetra-n-butylammonium fluoride and in situ acetylation of the phenols with acetic anhydride gave the acetoxy compounds 15l and 16l (Scheme IX). The cis and trans geometries of the stilbenes were assigned by the characteristic 1H NMR coupling constants of the olefinic protons. Catalytic hydrogenation of stilbenes 15 and 16 at about 40 psi in the presence of 10% palladium on charcoal gave the dihydrostilbenes 17a-e (Scheme XIII). The amino ethers 17f-g were prepared by the reaction of 1-(4-hydroxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethane (18) with dialkylaminoethyl chlorides 19a-b in refluxing acetone in the presence of K2CO 3 (Scheme X). Compounds 17h and 17i were prepared by the alkylation of 3,4,5-trimethoxyphenyl-acetonitrile (20a) and 4-methoxyphenylacetonitrile (20b) with 4-methoxybenzyl bromide (21a) and 3,4,5-trimethoxybenzyl bromide (21b), respectively, using LDA as the base (Scheme XI). Similarly, alkylation of methyl 4-methoxyphenylacetate (20b) with 3,4,5-trimethoxybenzyl bromide 21b gave product 17j.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(=O)(O)[O-].[Na+].O>[N:14]1([C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Clc1nc2cccc3c2n1CCC3
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: c1cc2c3c(c1)nc(N1CCOCC1)n3CCC2
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (2.50 g) in morpholine (15 ml) was heated under reflux, under nitrogen, with stirring. After one hr, the solution was diluted with sodium bicarbonate solution (100 ml) and water (100 ml). The aqueous solution was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by high performance liquid chromatography (silica gel; ethyl acetate). The appropriate fractions were collected and concentrated. The residue was crystallized from ether to give 2.1 g (67%) of product, mp 93°-94° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[N:40]1[CH:45]=[CH:44][N:43]=[CH:42][C:41]=1[C:46](Cl)=[O:47]>>[N:40]1[CH:45]=[CH:44][N:43]=[CH:42][C:41]=1[C:46]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:47]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1cnccn1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cnccn3)CN2C1=O
Yield: 52.5 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and pyrazinecarbonyl chloride (75 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 62 mg (52%) of 18-(pyrazinecarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.8% pure (HPLC), MS m/z 673 (M−H)−, HRMS: calcd. 675.2812 and found 675.2792 (M+H)+, mp 150-152° C.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)C>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.0 g, 0.0030 mol—Preparation 3), 4-carboxyphenylboronic acid (0.5 g, 0.0030 mol), sodium carbonate (0.64 g, 0.0060 mol) dioxane (60 mL), ethanol (10 mL) and water (10 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.106 g, 0.00015 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 90° C. for 2 hours. The volatiles were evaporated to provide a residue. The residue was stirred with water and acidified with 2 N hydrochloric acid to pH 5-6 to provide a precipitate. The precipitate was collected by filtration and dried under reduced pressure to afford the title compound (0.8 g, 71%). The compound was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 9.18 (d, J=2.4 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.10-8.03 (m, 4H), 4.58 (br s, 4H), 3.79 (t, J=4.5 Hz, 4H): LC-MS (ESI): Calculated mass: 370.0; Observed mass [M+H]+: 371.1 (RT=1.37 min).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:11][CH:10]=1)([OH:8])[CH3:7])C.[OH-].[Na+]>C(O)(C)C>[Cl:22][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]([OH:8])([CH3:7])[CH2:5][C:4]([OH:23])=[O:3])=[CH:14][CH:13]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(O)(CC(=O)O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 24 h

Procedure:
1 g. of 3-(3',4'-dichloro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester and 0.2 g. of NaOH in 40 ml. of isopropanol are left to stand for 24 hours and the mixture is worked up to give 3-(3',4'-dichloro-4-biphenylyl)-3-hydroxybutyric acid, m.p. 124°-126°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:14])([N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:5].[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[CH2:23][CH:22]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])[CH2:21][CH2:20]2>>[CH3:1][O:2][C:3](=[O:15])[C:4]([N:6]1[CH:10]=[C:9]([NH:11][C:30](=[O:31])[CH:29]([NH:28][CH:22]2[CH2:21][CH2:20][C:19]3[C:24](=[C:25]([F:27])[CH:26]=[C:17]([F:16])[CH:18]=3)[CH2:23]2)[CH2:33][CH2:34][CH3:35])[N:8]=[CH:7]1)([CH3:14])[CH3:5]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: COC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionic acid methyl ester was reduced and coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid to afford the title compound; MS 449.3 m/z (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[NH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C>O1CCOCC1>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)=[CH:15][C:14]=1[C:7]1[C:8](=[O:13])[N:9]([CH3:12])[C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH:11]=2
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: NCc1cccnc1
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(NCc3cccnc3)cc2n(C)c1=O
Reaction time: 14 h

Procedure:
N-[3-(7-Chloro-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (50 mg, 0.106 mmol) is mixed with 3-(aminomethyl)-pyridine (18 mg, 0.16 mmol), Pd2(dba)2 (2.4 mg, 2.5%), 1,3-Bis(2,6-di-i-propylphenyl)-imidazolium chloride (2.3 mg, 5%) and potassium tert-butanoxide (17.8 mg, 0.159 mmol) under an argon environment. 6 mL of anhydrous 1,4-dioxane is added and the reaction is continued at 100° C. for 14 hours. After cooling and removal of solvent under vacuum, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the final product as a pale solid: 1H NMR 400 MHz (DMSO-d6) δ 10.46 (s, 1H), 8.79 (s, 1H), 8.68 (d, 1H, J=4.6 Hz), 8.44 (s, 1H), 8.29 (s, 1H), 8.24 (t, 2H, J=7.5 Hz), 7.96 (d, 2H, J=7.8 Hz), 7.76 (m, 3H), 7.65 (m, 2H), 7.24 (d, 1H, J=8.3 Hz), 6.46 (s, 1H), 4.74 (s, 2H), 3.52 (s, 3H), 2.11 (s, 3H); MS m/z 544.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:18][CH2:19][OH:20])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.O>[CH3:24][S:21]([O:1][CH2:2][CH2:3][C:4]1([CH2:18][CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6][CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CCO)(CCO)CC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (1.1 ml, 8.36 mmol, 3.0 eq.) was added to a cooled solution of tert-butyl 4,4-bis(2-hydroxyethyl)azepane-1-carboxylate (800 mg, 2.78 mmol, 1.0 eq.) in methylene chloride (10 ml) at 0° C. and then mesylchloride (0.47 ml, 6.13 mmol, 2.2 eq.) was added to the reaction mixture and it was stirred at RT for 2 h. After completion (monitored by TLC), the reaction mixture was diluted with water (20 ml) and methylene chloride (100 ml). The organic part was separated and the water layer was extracted with methylene chloride (2×20 ml). The combined organic layers were washed with brine (20 ml), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2([C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.Cl.O>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH:23]([CH2:24][CH2:25][CH3:26])[OH:27])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)C1(CCCc2ccccc2)c2ccccc2-c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCC(O)C1(CCCc2ccccc2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 189 compound (400 mg, 1.13 mmol) in 25 ml of methanol was cooled to 0° C. under an argon atmosphere. Sodium borohydride (93 mg, 2.45 mmol) was added portion wise over 10 minutes and the mixture was then stirred for 30 min. longer at 0° C. The reaction was diluted with 0.1 N hydrochloric acid to pH 4. The reaction mixture was diluted with 30 ml of water and extracted with ethyl acetate (3×20 ml). The ethyl acetate extract was washed with water, brine and dried over sodium sulfate. The crude product was purified on a Merck EM silica column eluting with 10% ethyl acetate/hexane yielding 345 mg (86%) of title compound as a colorless oil.
Reaction SMILES: O[C:2]1[N:3]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:4](=[O:11])[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[N:10]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[N:3]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:4](=[O:11])[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[N:10]=1
Reactant: O=c1c2nc[nH]c2nc(O)n1-c1ccc(Cl)nc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1c2nc[nH]c2nc(Cl)n1-c1ccc(Cl)nc1
Temperature: 135 °C

Procedure:
2-Hydroxy-1-(6-chloropyridin-3-yl)-1,9-dihydro-6H-purin-6-one from the above reaction is suspended in a large excess of phosphorous oxychloride (150 mL) and heated to 135° C. for 24 h. The reaction mixture is cooled, evaporated in vacuo, and additional toluene is added and evaporated (2×) under reduced pressure. The resulting sticky brown oil is dissolved in DCM (200 mL), and then neutralized with saturated NaHCO3 (aqueous). The aqueous layer is extracted with DCM (2×200 mL) and dried (MgSO4). The dried extract is filtered and concentrated under vacuum to afford crude product as a light brown solid. The crude product is purified by flash column chromatography using 1-2.5% MeOH/CH2Cl2 to afford the title compound as white solid. 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.78 (s, 1H), 7.58 (d, J=6 Hz, 1H), 7.53 (d, J=6 Hz, 1H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])[N:15](CC2C=CC=CC=2)[CH2:14][C@H:13]1[CH3:32])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCO.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])[NH:15][CH2:14][C@H:13]1[CH3:32])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOC2=O)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H]1CN[C@@H](CN2CCOC2=O)CN1C(=O)OC(C)(C)C

Procedure:
Acetic acid (1.5 mL) and Pd/C (400 mg) were added to a solution of (2R,5S)-4-benzyl-2-methyl-5-(2-oxo-oxazolidin-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.15 mmol) in EtOH (20 mL) and the resulting mixture was reacted under H2 (1 bar) for 3 h. The catalyst was removed by filtration through a plug of Celite and the solvent was removed in vacuo to give the title compound (530 mg) as a colourless gum. MS: [M+H]+=300.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[Br:12]Br>C(#N)C>[NH2:1][C:2]1[C:7]([Br:12])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: BrBr
Solvent: CC#N
Product: Nc1c(O)cc([N+](=O)[O-])cc1Br
Temperature: 32.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-amino-5-nitro-phenol (500 g, 3.24 mol) in ACN (12 L) was added bromine (290 mL, 5.63 mol) drop wise over a period of 30 min. The mixture was stirred at 30-35° C. for 1 h, then the solvent was evaporated to dryness. Hexane (2 L) was added and the mixture evaporated to dryness. Hexane (5 L) was added and the mixture stirred for 1 h and filtered. The solid (1102 g) was washed with hexane (2 L). The residue was added to ice-cold H2O (2.5 L) followed by the addition of a saturated solution of sodium thiosulfate (2.5 L) and extraction with EtOAc (2×10 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated at 40-45° C. in vacuo to obtain i (643 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([NH:24][C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)[CH:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cc(F)cc2n1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cccc(CCN2CCN(c3cc(F)cc4nc(C)ccc34)CC2)c1
Yield: 46 %

Procedure:
The Title Compound was Prepared in 46% Yield According to the General Procedure for the preparation of amides (Method B) starting from 3-{2-[4-(7-fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline and acetyl chloride:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[ClH:21]>C(OCC)(=O)C.C(O)C.[Pd]=O>[ClH:21].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Oc2ccccc2)cc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(CS(=O)(=O)Oc2ccccc2)cc1

Procedure:
A solution of phenyl 4-nitrobenzenemethanesulphonate (1.6 g) in ethyl acetate (200 ml) and concentrated hydrochloric acid (1 ml) was hydrogenated over prereduced 5% palladium oxide on charcoal (50% aqueous paste 0.4 g) in ethanol (10 ml) at atmospheric pressure and temperature. The catalyst was filtered off and the filtrate concentrated to give the title compound as a solid (1.55 g). A small sample (0.2 g) was crystallized from isopropyl acetate (10 ml) and a few drops of methanol to give analytically pure material (70 mg) m.p. 147°-148°.
Reaction SMILES: C(O[C:4](=[O:17])[C:5](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[C:6]#[N:7])C.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>CO>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][N:8]=[C:5]([C:6]#[N:7])[C:4]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[O:17]
Reactant: CCOC(=O)C(C#N)=NNc1ccccc1Br
Reactant: CCCCN
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNC(=O)C(C#N)=NNc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a microwave vial charged with [(2-bromophenyl)-hydrazono]-cyanoacetic acid ethyl ester (387 mg, 1.31 mmol) was added methanol (3 mL) and n-butylamine (520 uL, 5.24 mmol). The reaction temperature rose approximately 30° C. and everything went into solution. After 25 minutes, additional n-butylamine (260 uL, mg, 2.6 mmol) and triethyl amine (182 uL, 1.3 mmol) were added. The reaction was stirred at room temperature overnight and then concentrated to afford the title compound which was used without further purification (420 mg, 99%). 1H NMR (300.132 MHz, CDCl3) δ 14.33 (s, 1H), 7.67 (dd, J=8.3, 1.5 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.34 (td, J=7.8, 1.2 Hz, 1H), 7.01 (dt?ddd, J=6.1 Hz, J=8.0 Hz, J=1.5 Hz, 1H), 6.22 (bs, 1H), 3.40 (dt, J=5.9, 7.2 Hz, 2H), 1.65-1.35 (m, 4H), 0.96 (td, J=7.3, 1.9 Hz, 3H). MS APCI, m/z=323/325 (M+H). HPLC 2.94 min
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:14][O:15][CH3:16])[C:10]([NH:12][CH3:13])=[O:11].[H-].[Na+].Cl[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23]([Cl:30])=[CH:22][N:21]=1.Cl>C1COCC1>[Cl:30][C:23]1[CH:24]=[C:25]([C:26]([F:29])([F:27])[F:28])[C:20]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11])=[N:21][CH:22]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: FC(F)(F)c1cc(Cl)cnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ncc(Cl)cc1C(F)(F)F
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
2-(2-Hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (300 mg) was dissolved in THF (5 ml). 60% Sodium hydride (65 mg) was added, and the mixture was stirred for 10 minutes. 2,5-Dichloro-3-trifluoromethylpyridine (350 mg) was added, and the mixture was stirred at room temperature for 12 hours, neutralized with 1N-hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to obtain the title compound (398 mg, yield: 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[C:29](=[O:46])[N:30]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]([CH3:37])=[N:32]2>CN(C=O)C>[O:45]=[C:39]1[CH:38]([N:30]2[C:29](=[O:46])[C:28]3[C:33](=[CH:34][CH:35]=[CH:36][C:27]=3[CH2:26][NH:25][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:32]=[C:31]2[CH3:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a stirred solution of (4-fluoro-phenyl)-acetic acid (0.23 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1′ carbonyldiimidazole (0.26 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-fluoro-phenyl)-acetamide as a white solid (480 mg, 76% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 5.83 min (99.2%); mp, decomposed at 290° C.; 1HNMR (DMSO-d6) 2.12-2.19 (m, 1H, CHH), 2.57-2.91 (m, 6H, CHCH2, CH3), 3.53 (s, 2H, ArCH2), 4.68-4.83 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.09-7.72 (m, 7H, Ar), 8.36 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.58, 41.36, 41.70, 56.48, 114.89 (d, JC-F=21 Hz), 117.69, 124.72, 125.58, 130.86 (d, JC-F=7 Hz), 132.45 (d, JC-F=3 Hz), 133.82, 140.68, 148.44, 154.80, 160.91, 161.00 (d, JC-F=242 Hz), 169.50, 170.15, 172.59. LCMS MH=437; Anal Calcd For C23H21N4O4F: C, 63.30; H, 4.85; N, 12.84; F, 4.35. Found: C, 63.25; H, 4.66; N, 12.73; F, 4.21.