Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]([C:20]1[N:21]=[CH:22][N:23]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]=1[CH3:25])[CH:6]1[C:18](=[O:19])[N:10]2[C:11]3[C:16]([CH:17]=[C:9]2[CH2:8][CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH3:25][C:24]1[N:23]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:22]=[N:21][C:20]=1[CH:5]=[C:6]1[C:18](=[O:19])[N:10]2[C:11]3[C:16]([CH:17]=[C:9]2[CH2:8][CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2cc3ccccc3n2C1=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(C=C2CCc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one in toluene (30 ml) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (762 mg). After being stirred at 55° C. for 2 hours, the solution was evaporated in vacuo. The residue was diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue obtained was purified with silica gel column chromatography (eluent:chloroform) to give 8,9-dihydro-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.3 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[C:3]=1[OH:15].Br[CH2:17][CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[C:3]=1[O:15][CH2:19][CH:18]=[CH2:17]
Reactant: Cc1c(C(=O)O)cc(C(=O)O)c(C)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(C)c(C(=O)O)cc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
2.400 g (11.42 mmol) of dimethyl 5-hydroxyisophthalic acid, 1.4 g (11.6 mmol) of 3-bromopropene and 1.6 g (11.6 mmol) of potassium carbonate were dispersed in 40 ml of acetone and stirred for 15 hours at reflux temperature. The mixture was cooled to room temperature and filtered off insoluble salts after the addition of 150 ml of diethylether. The filtrate was concentrated and purified through the silicagelcolumn chromatography (developing solvent: diethylether/hexane=½), 2.612 g of dimethyl 5-allyloxyisophthalic acid in water-white solid powder was obtained (yield: 94.1%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:40])[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:45][CH2:46][N:41]([CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-isopropyl-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O2 [(M+H)+] 650.3023, observed 650.3022.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[C:17]2[NH:16][C:15]([CH3:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH2:19]([O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[CH3:20]>O>[Cl:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][C:25]4[CH:35]=[CH:36][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=4)=[CH:28][CH:29]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc2cccc(Cl)c2[nH]1
Reactant: CCOc1ccc(Oc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4c(Cl)cccc43)cc2)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a mixture of anhydrous N,N-dimethylforamide (10 ml) and sodium hydride (62% oil suspension; 0.071 g), 4-chloro-2-methylbenzimidazole (0.304 g) was added while stirring, and the stirring was continued at room temperature for 1 hour. The resultant mixture was cooled to 5°-10° C., and a solution of 4-(4-ethoxyphenoxy)benzyl chloride (0.400 g) in anhydrous N,N-dimethylformaide (10 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene extract was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 4-chloro-1-[4-(4-ethoxyphenoxy)benzyl]-2-methylbenzimidazole (0.204 g) as a colorless liquid. nD26.5 1.6087.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Br)=[CH:3][CH:2]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[C:4]1([CH2:7][CH2:8][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: C1CNCCN1
Reactant: BrCCc1ccccc1
Product: c1ccc(CCN2CCNCC2)cc1
Yield: 92 %

Procedure:
Using β-phenethyl bromide and piperzine, the procedure of Reference Example 16 was otherwise repeated to provide the title compound. Yield 92%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:19])=[C:16]([F:18])[F:17])=[CH:11][C:10]=2[O:20]C)[N:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:19])=[C:16]([F:17])[F:18])=[CH:11][C:10]=2[OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(F)=C(F)F)ccc1Oc1cccc(F)n1
Agent: BrB(Br)Br
Product: Oc1cc(C(F)=C(F)F)ccc1Oc1cccc(F)n1
Yield: 64 %

Procedure:
According to the procedure of example 5 (b) except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by 2-fluoro-6-[2-methoxy-4-(trifluorovinyl)phenoxy]pyridine (0.033 mmol; 10 mg) and adding 3.5 equivalents (0.117 mmol; 117 μl) of boron tribromide, the title compound was prepared in 64% yield (0.021 mmol; 6 mg) after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[CH:17]=CC(C#C)=CN=1>>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1)#[CH:17]
Reactant: C#Cc1ccc(Cl)nc1
Reactant: CN(C)c1ccc(I)cn1
Product: C#Cc1ccc(N(C)C)nc1

Procedure:
(5-Ethynyl-pyridin-2-yl)-dimethyl-amine was prepared from (5-iodo-pyridin-2-yl)-dimethyl-amine in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:4].[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=[O:40])([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)Cn1ccnc1C=O
Yield: 62.5 %

Procedure:
A solution of di-tert-butyl 4-(2-bromoacetamido)-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (1.397 g, 2.61 mmol), 1H-imidazole-2-carbaldehyde (0.30 g, 3.13 mmol), DIPEA (2.0 mL), and KI (0.30 g) in DMF (5.0 mL) was stirred at 80° C. for 5 hrs. The solvent was evaporated under reduced pressure to afford a residue, which was purified by biotage eluting with 20% EtOAc in hexanes to 100% EtOAc to give di-tert-butyl 4-(3-(tert-butoxy)-3-oxopropyl)-4-(2-(2-formyl-1H-imidazol-1-yl)acetamido)heptanedioate (0.90 g, 63%). 1H NMR (400 MHz, CDCl3) 9.78 (s, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 6.65 (s, 1H), 4.90 (s, 2H), 2.19 (t, J=7.8 Hz, 6H), 1.94 (t, J=7.8 Hz, 6H), 1.42 (s, 9H); MS (ESI), 552 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:9])=[C:4]2[C:6]([CH:10]=[CH:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: O=C/C=C/c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1c(Cl)ccc2ccc(-c3ccccc3)nc12

Procedure:
To a stirred solution of 3-chloro-2-fluoroaniline (2.9 g, 20 mmol) and trans-cinnamaldehyde (2.64 g, 20 mmol) in toluene (25 ml) was added 6N HCl (100 ml). The resulting suspension was heated at reflux for 40 hours. After cooling, the reaction mixture was poured into 5N NaOH solution (200 ml) and extracted with EtOAc (3×100 ml). The combined organics were washed with brine (2×100 ml), dried (MgSO4), filtered and concentrated. The crude product was dissolved in MeOH and loaded onto an SCX-2 cartridge (50g/150 ml), and the product eluted with MeOH, giving the title compound as a yellow solid. Additionally, the title compound could be prepared as follows: 4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline (6.0 g, 0.018 mole) and THF (240 mL) were combined in a 3 neck 1 L round bottom flask with a magnetic stir bar under an atmosphere of nitrogen. The reaction was stirred and cooled with a THF/liquid nitrogen bath to −100° C. 2.5 M of n-butyllithium in Hexane (7.34 mL) was then added dropwise over 3 minutes so as not to exceed −90° C. The solution turned light green, and darkened over a few minutes. Acetic acid (1.22 mL, 0.0214 mole) was added 3 minutes after the n-butyllithium addition was done. The cooling bath was removed, and the reaction was allowed to stir for 20 minutes. To work up, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was transferred to a 1 L separatory funnel with 250 mL of ethyl acetate. The layers were separated, and the organic layer was washed with 2×60 mL of brine. The organic solution was suction filtered through a short pad of silica gel, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was placed under high vacuum overnight to afford the crude product. The crude product was pre-adsorbed on 55 mL of Silica gel from methylene chloride. 100 mL of Toluene was added, and the slurry was concentrated on the rotovap to afford a finely divided powder. This was applied to a silica column and chromatographed (4:3 hexanes/methylene chloride) affording the title compound as a white solid. The solid was re-chromatographed with, and then placed in the vacuum oven at 45° C. overnight to afford the very pure product as a white solid; 1H NMR (CDCl3, 400 MHz) δ 8.24-8.21 (3H, m), 7.96 (1H, d, J=8.6Hz), 7.58-7.48 (5H, m); MS (ES+): m/z 258.13 [MH+]; HPLC: tR=3.64 min (MicromassZQ, non-polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:20])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([O:20][CH3:30])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(OC)cccc21
Temperature: 60 °C
Reaction time: 13 h
Yield: 55.1 %

Procedure:
A mixture of 3-(4-fluorobenzoyl)-7-hydroxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (65 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), methyl iodide (0.4 mL, 6.4 mmol) and dry acetone (5 mL) was stirred at 60° C. for 13 hours. The potassium carbonate solid was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-EtOAc (90:10) to give the title compound as a yellow solid (36 mg, 55%); 1H-NMR (CDCl3): δ 10.56 (1H, s), 7.98 (1H, s), 7.64-7.59 (2H, m), 7.18-7.12 (3H, m), 7.03 (1H, t), 6.64 (1H, d), 4.28-4.19 (4H, m), 3.96 (3H, s), 3.26-3.24 (2H, m), 1.24 (3H, t); MS (ES): 409 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].[C:31]1([O:38][CH3:39])[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33]>CC(C)=O>[CH3:39][O:38][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[O:33][C:2]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23]
Reactant: COC(=O)c1cc(OCCOC2CCCCO2)c(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCOC2CCCCO2)c(Oc2ccccc2OC)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
4.28 g of methyl 4-chloro-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in acetone (250 ml), treated at RT with 5.0 g of potassium carbonate, 1.93 of guaiacol and the mixture was heated at reflux for 20 hours. It was poured on to ice-water and extracted with ethyl acetate. The organic phase was washed 3 times with 5% sodium hydroxide solution, then with water, dried over sodium sulphate and finally concentrated on a rotary evaporator. The crude product (6 g) was flash chromatographed on silica gel with hexane/ether (1/1). There was thus obtained the desired methyl 4-(2-methoxy-phenoxy)-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a pale yellow powder.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(Cl)Cl.O>[CH:19]1([NH:22][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[N+:10]([O-:12])=[O:11])[C:5]#[N:6])[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c(NC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-fluoro-4-nitrobenzonitrile (2.0 g, 0.012 mol) in DCM (20 ml), was added K2CO3 (3.3 g, 0.024 mol) and cyclopropyl amine (6.7 ml, 0.096 mol) and the resulting solution was continued to stir at room temperature for 3 h. The reaction was diluted with cold water and extracted with dichloromethane (3×100 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound 3-(cyclopropylamino)-4-nitrobenzonitrile as a yellow solid. 1H NMR (400 MHz, CDCl3), δ: 8.24-8.22 (d, J=8.8 Hz, 1H), 8.07 (bs, 1H), 7.64 (s, 1H), 6.94-6.92 (d, J=8.8 Hz, 1H), 2.59-2.58 (m, 1H), 1.25-0.97 (m, 2H), 0.71-0.58 (m, 2H). MS (M+1): 204.
Reaction SMILES: Br[CH2:2][CH3:3].[Cl:4][C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH2:16][CH3:17])[N:6]=1>>[Cl:4][C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[N:14]([CH2:2][CH3:3])[C:9]=2[N:8]=[C:7]([CH2:16][CH3:17])[N:6]=1
Reactant: CCBr
Reactant: CCc1nc(Cl)c2c(n1)NC(=O)CO2
Product: CCc1nc(Cl)c2c(n1)N(CC)C(=O)CO2

Procedure:
Using the procedure of Example 80, except that 1-bromoethane was used instead of methyl iodide, 4-chloro-6,7-dihydro 2-ethyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one was alkylated providing 4-chloro-2,8-diethyl-6,7-dihydropyrimido[5,4-b][1,4]oxazin-7-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/B(O)O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][C:3]=2[CH3:20])=[CH:24][CH:23]=1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2C(N)=O)ccc1Br
Reactant: OB(O)/C=C/c1ccc(F)cc1
Product: Cc1cc(S(=O)(=O)c2ccccc2C(N)=O)ccc1/C=C/c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-[(4-bromo-3-methylphenyl)sulfonyl]benzamide (Step 1) and [(E)-2-(4-fluorophenyl)vinyl]boronic acid according to the method of Example 1 Step 4. m/z (ES+) 379 [(M-NH2)+].
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[S:11](Cl)([Cl:13])=[O:12]>>[Cl:13][S:11]([O:8][CH:3]([CH2:4][C:5]([CH3:7])=[CH2:6])[C:2]([Cl:10])([Cl:9])[Cl:1])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Product: C=C(C)CC(OS(=O)Cl)C(Cl)(Cl)Cl

Procedure:
To 20.35 g of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene was added 23.8 g of thionyl chloride. The resulting solution was heated at 80°-90° for one hour. After cooling, the excess thionyl chloride was removed under reduced pressure. The residue was fractionally distilled. A fraction weighing 5.9 g; bp, 100°/2.8 mm, was analyzed by vapor phase chromatography and mass spectrometry. The major component of the fraction was identified as 1,1,1-trichloro-4-methyl-4-penten-2-yl chlorosulfinate.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][OH:24].[OH-].[Na+].Cl>C1COCC1.CO>[OH:24][NH:23][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][NH:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: NO
Reactant: COC(=O)c1ccc(OCCNC(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccc(OCCNC(=O)c2ccccc2)cc1
Reaction time: 14 h

Procedure:
To a solution of crude methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate (0.5 mmol) in a 1:1 mixture of THF/methanol (20 ml) was added 50 wt. % aqueous hydroxylamine (3 ml) followed by 1M aqueous NaOH (1 ml) adjusting the pH between 10-11. The reaction mixture was stirred for 14 h, neutralized to pH=7-8 with 6 M aqueous HCl and concentrated in vacuo. The precipitate was collected and purified by HPLC providing the title compound as a white solid. 1H NMR (DMSO-d6): δ 8.69 (t, J=5.8 Hz, 1H), 7.83 (d, J=7.5 Hz, 2H), 7.69 (d, J=9.1 Hz, 2H), 7.46 (m, 3H), 6.99 (d, J=9.1 Hz, 2H), 4.16 (t, J=5.8 Hz, 2H), 3.63 (q, 5.8 Hz, 2H). EM (calc.): 300.1; MS (ESI) m/e: 301.1 (M−1)+, 299.0 (M+1)−.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:44])=[C:5]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]2C(=O)C3=CC=CC=C3C2=O)=[O:25])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].O.NN>>[CH3:1][C:2]1[NH:3][C:4]([CH3:44])=[C:5]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])=[O:25])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9]
Reactant: CC1=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC(C)C)=C(C)N1
Agent: NN
Solvent: O
Product: CC1=C(C(=O)OCCCCCCN)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC(C)C)=C(C)N1

Procedure:
Prepared by a method analogous to that of Example 1(b) from 13.28 g (22 mmol) of 1,4-dihydro-2,6-dimethyl-3-isobutoxycarbonyl-4-(3-nitrophenyl)-5-(6-phthalimidohexyloxy)carbonyl-pyridine and 3.3 ml (66 mmol) of hydrazine hydrate. 9.02 g (86%) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:23])=[CH:20][N:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2)nc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (100 mg, 0.69 mmol) and 6-phenylnicotinic acid (D48) (198 mg, 1 mmol) as a solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (d, 1H), 8.92 (dd, 1H), 8.33 (dd, 1H), 8.23 (s, 1H), 8.15, (d, 1H), 8.14 (s, 1H), 8.08 (m, 3H), 7.90 (d, 1H), 7.87 (d, 1H), 7.50 (m, 3H), 7.38 (dd, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.B(Cl)(Cl)[Cl:25].CO>ClC(Cl)C>[ClH:25].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1
Reactant: ClB(Cl)Cl
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Agent: Cl
Solvent: CO
Solvent: CC(Cl)Cl
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A slurry of 10 g (25 mmol) of 1-aminomethyl-3,4-dihydro-5,6-dimethoxy-3-phenyl-naphthalene hydrochloride, from Step 2, in 150 mL of dichloroethane was cooled to 10° C. under a nitrogen atmosphere. Boron trichloride was passed through the reaction mixture until 27 g (230 mmol) had been added. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then recooled in ice and 100 mL of methanol was added dropwise. The reaction mixture was again allowed to warm to ambient temperature and concentrated in vacuo. Twice, 500 mL portions of methanol were added to the residue and it was reconcentrated. The resultant foam was dissolved in 40 mL of ethanol, filtered and the solution was treated with 40 mL of methylene chloride and 80 mL of heptane. Off-white crystals of 1-aminomethyl-3,4-dihydro-5,6-dihydroxy-3-phenyl naphthalene hydrochloride (5.1 g, 56% yield) were collected by filtration, m.p. 204°-205° C. The 1H NMR spectrum was identical to the spectrum for the product of Example 2A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[O:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22][O:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:4][C:3](=[O:16])[O:2][CH3:1])[CH:14]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)Oc1cc(O)c2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Oc1cc(OCOCC[Si](C)(C)C)c2ccccc2c1
Temperature: 2 °C
Reaction time: 48 h
Yield: 75.4 %

Procedure:
4.62 g (21.2 mmol) of carbonic acid 4-hydroxy-naphthalen-2-yl ester methyl ester [Journal of Agricultural and Food Chemistry (1994), 42(12), 2970-2] was dissolved in 150 ml of MeCl2, 4.95 ml=4.71 g (25.4 mmol) of 2-(trimethylsilyl)-ethoxymethylchloride was added and this mixture cooled down to 2° C. 11.1 ml=8.38 g (63.5 mmol) of N-ethyl-diisoproylamine was added drop by drop and then, reaction was warmed up to ambient temperature. After 48 hours, it was poured into crashed ice and extracted twice with MeCl2; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of n-heptane/MeCl2) to give 5.57 g of carbonic acid methyl ester 4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-yl ester as colorless oil.