Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH:13](=O)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:13]=1[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1nccs1
Reactant: O=Cc1ccco1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccco2)nc2sccn12

Procedure:
Compound 2 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) furfural solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([NH2:24])=[O:23].[Br:25][C:26]1[CH:45]=[CH:44][C:29]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][C:37](O)=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[C:28]([F:46])[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:67]>>[ClH:67].[Br:25][C:26]1[CH:45]=[CH:44][C:29]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][C:37]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22](=[O:23])[NH2:24])=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[C:28]([F:46])[CH:27]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: ClCCl
Reactant: NC(=O)[C@@H]1CCCN1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCN1CCC[C@H]1C(N)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of diethyl azodicarboxylate (209 mg, 1.2 mmol) in methylene chloride (1 ml) and then (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0.4 mmol), (prepared as described for the starting material in Example 48), and triphenylphosphine (314 mg, 1.2 mmol) in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature and further triphenylphosphine (109 mg, 0.4 mmol) and (S-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (40 mg, 0.23 mmol) were added followed by the dropwise addition of diethyl azodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 30 minutes at ambient temperature and further (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (34 mg, 0.2 mmol) was added. The mixture was then stirred for 2 hours at ambient temperature and the mixture was purified by pouring directly onto a column of silica and eluting with methylene chloride/ethyl acetate/methanol (60/35/5). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and 3M hydrogen chloride in ethyl acetate (0.4 ml) was added. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum to give (S)-4-(4-bromo-2-fluoroanilino)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-6-methoxyquinazoline hydrochloride (110 mg, 47%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:12][OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N([Cl:23])C(=O)C1>CN(C=O)C>[OH:13][N:12]=[C:11]([Cl:23])[C:9]1[CH:8]=[CH:7][C:6]2[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=2[CH:10]=1
Reactant: CC1(C)OB(O)c2ccc(C=NO)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (8 mg, 0.039 mmol) in DMF (1.0 mL) at rt was added NCS (6.2 mg, 0.047 mmol). The reaction mixture was stirred for 2 h, warmed to 40° C. and stirred for 3 h. The mixture was cooled to rt, poured into ice-water (10 mL) and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (8 mg; yield 86%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 12.50 (s, 1 H), 7.90 (s, 1 H), 7.70-7.79 (m, 2 H), 1.61 (s, 6 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][OH:15])[CH:6]=[CH:5]2.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C(Cl)Cl>>[C:19]([O:15][CH2:14][CH2:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[N+:16]([O-:18])=[O:17])[C:8]1=[O:12])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2ccc(Cl)c([N+](=O)[O-])c2ccn1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCn1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 6-chloro-2-(2-hydroxyethyl)-5-nitroisoquinolin-1(2H)-one (400.0 mg, 0.00149 mol), acetic anhydride (0.21 mL, 0.0022 mol), pyridine (0.18 mL, 0.0022 mol) and methylene chloride (20 mL, 0.2 mol) and the reaction stirred at room temperature over night. The solvent was removed to obtain the product as a yellow solid. MS m/z=311.3 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:18][OH:19].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:19][NH:18][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2ncc(C(=O)NO)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15a (125 mg, 0.518 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (360 mg, 5.18 mmol) and a freshly prepared solution of sodium methoxide in methanol (178 mg, 7.72 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16a. HPLC: (Rt=10.74 min).
Reaction SMILES: Br[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][O:11]1)=[O:10].[K].CCOCC.O.C[N:27](C)C=O>>[O:10]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:11])[N:27]1[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)Br
Reactant: CN(C)C=O
Reactant: O=C1OCc2ccccc21
Agent: [K]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(F)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C

Procedure:
A stirred mixture of ethyl bromofluoroacetate (1.0 g, 5.4 mmol) and potassium phthalide (1.0 g, 5.4 mmol) in dimethylformamide (10 mL) is heated at 80° C. for 3 hours. The mixture is stirred with ether (50 mL) and water (50 mL) and the organic layer then washed with water and brine (30 mL each), and dried over sodium sulfate. The solvent is removed in vacuo to give ethyl 2-(1,3-dioxoisoindolin-2-yl)-2-fluoroacetate which is further purified through chromatography.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH2:14][OH:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.C(#N)C.[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C>O>[C:24]([O:15][CH2:14][CH:13]([C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[C:3]3[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=3[CH:5]=[CH:6][C:7]=2[CH:12]=1)[CH3:16])(=[O:26])[CH3:25]
Reactant: CC(CO)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCC(C)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
0.5 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propan-1-ol is dissolved in 15 ml. of acetonitrile and 2 ml. of acetyl chloride and 1.3 ml. of triethylamine are added to the solution. After 1 hour, the mixture is poured into water and extracted with ethyl acetate. The extract is dried and evaporated, then dissolved in ether and passed through a silica gel column, and the eluate evaporated to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl acetate [an oil, nmr spectrum in deuterochloroform relative to tetramethylsilane, 1.33 (doublet, CH3), 1.98 (singlet, acetoxy), 4.23 (doublet, CH2) and 7.02 ppm (singlet, 10H, 11H); mass spectrum: 306 (M+), 246, 234].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.N1CCCCC1>CCO>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C

Procedure:
A general procedure for the preparation of 3-benzylideneindolin-2-ones: A mixture of 5-fluoroindolin-2-one (151 mg, 1 mmol), 4-(dimethylamino)benzaldehyde (149 mg, 1 mmol), and piperidine (12.7 mg, 0.15 mmol) in 4 mL EtOH was heated at reflux for 15 h and cooled to rt. The solid was collected via filtration and washed with ether (10 mL), and dried under vacuum. The crude product was further purified with silica chromatography (hexane/EtOAc) to afford 3-(4-(dimethylamino)benzylidene)-5-fluoroindolin-2-one as a orange solid (220 mg, 78%, E/Z ratio 7:1). For the major E/Z isomer: 1H NMR (400 MHz, acetone-d6) δ 9.41 (s, 1 H), 7.68-7.64 (m, 3 H), 7.58 (dd, J=9.6, 2.4 Hz, 1 H), 6.98-6.86 (m, 4 H), 3.09 (s, 6 H); MS (ESI) m/z 283 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:3]1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[CH3:1][C@@H:2]1[N:7]([S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 67 was prepared as described in general Method F. (S)-1-(3-methylpiperazin-1-yl)-4-phenylphthalazine (JK-8) (150 mg, 0.493 mmol) was dissolved in DMF (3 mL) and N,N-diisopropylethylamine (0.400 mL). Benzenesulfonyl chloride (104 mg, 0.591 mmol) was added and the reaction stirred at rt for 18 hours. The reaction was taken up in ethyl acetate (75 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a brown oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave 67 as an off-white solid. MS (M+H)+=445.2
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.C1COCC1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])=O.[Na+].[Na+].O>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(-c3cccc(CO)c3)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncnn2c(-c3cccc(CO)c3)cc(Br)c12
Reaction time: 1 h
Yield: 191.9 %

Procedure:
The product from step 1 (1.54 g, 6.4 mmol) was dissolved in 18 mL of 1:1 DMF:THF. The mixture was cooled to −20° C. (internal temperature) and 1,3-dibromo-5,5-dimethylhydantoin (0.92 g, 3.2 mmol) was added in 4 equal portions over 40 minutes. The mixture was stirred for an additional 1 hour during which the internal temp rose to −5° C. A solid mass formed, which was diluted with a mixture of 15 mL of 2M Na2CO3, 10 mL of sat. Na2SO3 and 60 mL of water and the mixture was stirred for an additional 30 minutes. The solid was collected by filtration, washed with water and dried in a vacuum oven at 40° C. to give 1.96 g (95%) of the title compound as a tan solid. 1H-NMR (DMSO-d6) 8.10 (bs, 1H), 7.94 (s, 2H), 7.86 (d, 1H), 7.40 (t, 1H), 7.29 (d, 1H), 7.17 (s, 1H), 6.84 (bs, 1H), 5.22 (t, 1H), 4.56 (d, 2H); LC-MS [M+H]+=319.3, 321.1, RT=2.29 min.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[NH2:33][C:34]1[CH:46]=[C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>ClCCl>[CH3:53][N:50]1[CH2:51][CH2:52][CH:47]([C:45]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])=[C:34]([NH:33][CH:11]3[CH2:12][CH2:13][O:8][CH2:9][CH2:10]3)[CH:46]=2)[CH2:48][CH2:49]1
Reactant: O=C1CCOCC1
Reactant: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(NC3CCOCC3)c2)CC1
Yield: 87.6 %

Procedure:
7.18 mL of 2,2,2-trifluoroacetic acid (93 mmol), 4.11 mg of dihydro-2H-pyran-4(3H)-one (44.5 mmol) and then 14.5 g of tetramethylammonium triacetoxyborohydride (53.8 mmol) are successively added to a solution of 15 g of tert-butyl 2-amino-4-(1-methylpiperidin-4-yl)benzoate in 200 mL of dichloromethane under stirring. The reaction medium is stirred at room temperature for 2 h and then taklen up with a 1N soda solution. The organic phase is isolated, dried on magnesium sulfate and then dried concentrated. The residue contained always HI. It is thus taken up in dichloromethane and washed with 100 mL of a 1H soda solution. The organic phase is decanted, dried on magnesium sulfate and dry concentrated to yield 14.6 g of a yellow solid (quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]([CH3:25])[CH2:14][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[CH2:16][NH2:17]>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[CH2:14][CH:13]([CH3:25])[CH3:12])=[O:6]
Reactant: Cc1ccc(C(CN)CC(C)C)cn1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1ccc(C(CNC(=O)c2cccc(C)c2C)CC(C)C)cn1

Procedure:
From 2,3-dimethylbenzoic acid and 4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH+): m/z=325.0, tR (minutes, Method A)=1.38
Reaction SMILES: O[C:2]1C=CC2C(=O)[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1CCC.C(OC(=O)CC[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:31]=1)=[O:29])C.C(=O)([O-])[O-:43].[K+].[K+]>CC(=O)CC>[CH2:8]([O:9][C:4](=[O:43])[CH2:3][CH2:2][C:27]1[CH:22]=[C:23]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:31]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1)[CH3:7]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCc1ccccc1C(=O)c1cccc(C(=O)OCC)c1
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCc1cccc(C(=O)c2cccc(C(=O)OCC)c2)c1

Procedure:
A mixture of 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 0.371 g (0.70 mmol) of 2-[(6-bromohexyl)oxy]-5[[(3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, 0.479 g (3.47 mmol) of anhydrous granular potassium carbonate and 13.1 mL of 2-butanone was stirred and refluxed for 18 hr. The resulting slurry was filtered with suction and the solids washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 3:1 hexane-ethyl acetate, giving 0.37 g (80.6%) of 2-[6-[2,3-dihydro-4-oxo-8-propyl-4H-1-benzopyran-7-yl)oxy]hexyloxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester as a white solid, mp 58°-59.5° C. A mixture of 0.331 g (0.50 mmol) of this ester in 6 mL of THF and 6 mL of water was treated with 64.7 mg (1.54 mmol) of lithium hydroxide monohydrate and the resulting mixture was stirred for 25.5 hr at room temperature, before being acidified with 17 mL of 3N aqueous sulfuric acid. Work-up with ethyl acetate in the usual manner gave a crude product which was recrystallized from hexane-ethyl acetate affording 0.242 g (79.7%) of the title compound as a white solid, mp 169°-172° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[O:42]1[C:46]2[CH:47]=[CH:48][C:49]([OH:51])=[CH:50][C:45]=2[O:44][CH2:43]1>>[O:42]1[C:46]2[CH:47]=[CH:48][C:49]([O:51][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:16])[CH2:11][CH:10]4[O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]5[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=5[CH:41]=4)=[CH:5][CH:4]=3)=[CH:50][C:45]=2[O:44][CH2:43]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4ccc5c(c4)OCO5)cc3)cc21

Procedure:
Analogously to Method I, 0.150 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.0548 g of benzo[1,3]dioxol-5-ol are reacted. The title compound is obtained as a yellowish oil. Rf=0.18 (1:2 EtOAc-heptane); Rt=5.78.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: COC(CNCc1ccc(F)cc1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Yield: 66.6 %

Procedure:
20 g (2,2-Dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (21) were dissolved in 120 ml of dichloromethane. 20 mL of pyridine are added. At 0° C. a solution of 23.8 g p-toluenesulfonic acid chloride in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring is continued until conversion was completed. For workup, the reaction mixture was extracted twice with 2M hydrochloric acid, twice with sodium bicarbonate and once with brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield 22.95 g of compound 22 as an orange oil. Rt=1.71 min (Method # 4). Detected mass: 336.1 (M-OMe−).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.Cl[C:10]1[CH:15]=[C:14]([F:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[NH:20][CH2:21][C:22]1[C:23]([NH:32][CH2:33][CH3:34])=[CH:24][C:25]([N:28]([O:30][CH3:31])[CH3:29])=[N:26][CH:27]=1.[CH3:35]CN(CC)CC>>[CH2:33]([N:32]1[C:23]2[CH:24]=[C:25]([N:28]([O:30][CH3:31])[CH3:29])[N:26]=[CH:27][C:22]=2[CH2:21][N:20]([C:11]2[CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[C:14]([F:16])=[CH:15][C:10]=2[CH3:35])[C:4]1=[O:3])[CH3:34]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1cc(N(C)OC)ncc1CNc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CCN(CC)CC
Product: CCN1C(=O)N(c2cc([N+](=O)[O-])c(F)cc2C)Cc2cnc(N(C)OC)cc21
Yield: 72.2 %

Procedure:
Diphosgene (2.4 mL, 19 mmol), 5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (6 g, 16 mmol) and Et3N (4.6 mL, 32 mmol) were combined by the procedure of Example A4 step 3 to provide 1-ethyl-3-(4-fluoro-2-methyl-5-nitro-phenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (4.5 g, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=8 Hz, 1 H), 7.94 (s, 1 H), 7.58 (d, J=12 Hz, 1 H), 6.58 (s, 1 H), 4.89 (d, J=16 Hz, 1 H), 4.48 (d, J=16 Hz, 1 H), 3.84-3.92 (m, 2H), 3.73 (s, 3 H), 3.16 (s, 3 H), 2.20 (s, 1 H), 1.19 (t, J=8 Hz, 3 H); MS (ESI) m/z: 390.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14]([C:16]1[CH:37]=[CH:36][C:19]([O:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]([C:31]([O-:33])=[O:32])[CH2:26][CH2:27][O:28]4)=[CH:23][C:22]=3[C:34]#[N:35])=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2.O[Li].O.O1CCOCC1.Cl>C1COCC1>[C:34]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:21]=1[O:20][C:19]1[CH:18]=[CH:17][C:16]([C:14](=[O:15])[NH:13][CH:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:9]3)=[CH:37][CH:36]=1)[O:28][CH2:27][CH2:26][CH:25]2[C:31]([OH:33])=[O:32])#[N:35]
Reactant: COc1ccc2c(c1)CCC(NC(=O)c1ccc(Oc3cc4c(cc3C#N)C(C(=O)[O-])CCO4)cc1)C2
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(NC(=O)c1ccc(Oc3cc4c(cc3C#N)C(C(=O)O)CCO4)cc1)C2
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.6 %

Procedure:
7-(4-((6-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (29.5 mg, 0.0576 mmol) was dissolved in THF (3 ml) and 1M solution of LiOH—H2O (115 μL, 0.115 mmol) was added. The mixture was stirred for 17 hours at ambient temperature. The mixture was quenched with 4M HCl dioxane (43.2 μL, 0.173 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 28.9 mg of the title compound as a thin film (100%). MS (apci) m/z=499.1 (M+H).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:13]1(=[O:19])[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1>CCOCC>[O:7]([C:8]([N:17]1[C:13](=[O:19])[CH2:14][CH2:15][C:16]1=[O:18])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C1CCC(=O)N1C(=O)Oc1ccccc1
Reaction time: 1 h

Procedure:
To 50 millimolses of phenylchloroformate in 25 ml of ether are added 16.7 ml of a 3M potassium hydroxide solution containing 50 millimoles of predissolved succinimide. The system is then stirred for about 1 hour, additional ether added and then restirred for about 1 hour. The insolubles formed are removed by filtering. Thereafter, the crude product is recrystallized from butanol saturated with water to give the desired product, melting point 132° - 133.5°C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:14][CH:13]=1.O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(CCCCCCCCCCBr)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(CCCCCCCCCCNc2ccc(C#N)cc2)cc1
Temperature: 120 °C

Procedure:
4-Aminobenzonitrile (11.8 g.) and 10-(4-methoxyphenyl)decylbromide (16.3 g.) are dissolved in hexamethylphosphoramide (100 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water (100 ml.) is added gradually. The mixture is then chilled in an ice bath. The precipitate separated is filtered, washed thoroughly with water, and dried. It is then washed repeatedly with hexane and dried. Recrystallization from ether-hexane affords 4-[10-(4-methoxyphenyl)decylamino]benzonitrile as pale yellow crystals.