Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[C:5]([C:17]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[O:18])=[C:4]([CH3:24])[NH:3]1.[H-].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1.[Na+].[Cl-]>[CH3:1][C:2]1[N:7]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[C:5]([C:17]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[O:18])=[C:4]([CH3:24])[N:3]=1
Reactant: CC1=C(C(=O)OCC2CC2)C(c2ccccc2[N+](=O)[O-])=NC(C)N1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1C(C)=NC(C)=C(C(=O)OCC2CC2)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
270 mg (0.82 millimole) of 2,6-Dimethyl-5-cyclopropylmethoxycarbonyl-4-(2-nitrophenyl)-dihydropyrimidine in 4 ml of anhydrous tetrahydrofuran was added to 47 mg (0.98 millimole) of sodium hydride as 50% suspension in oil and stirred at room temperature for 5 minutes. Ethyl chloroformate (120 μl), 1.32 millimole) was added and stirred at room temperature for 30 minutes. The reaction solution was diluted with saturated aqueous NaCl solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified on silica gel by thin layer chromatography (developer:chloroform/acetone 10:1, eluant : chloroform/methanol 4:1) to obtain 196 mg (yield 60%) of title compound.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[C:11]([O:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][CH2:27][OH:28])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:11]([O:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]\[CH2:27][OH:28])[CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)COc1cccc(C#CCO)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CC(C)(C)OC(=O)COc1cccc(/C=C\CO)c1
Reaction time: 1 h
Yield: 76 %

Procedure:
Quinoline (54 μL) and a Lindlar catalyst (54 mg) were added to a stirred solution of [3-(3-hydroxyprop-1-ynyl)phenoxy]acetic acid tert-butyl ester (547 mg, 2.09 mmol) in methanol (4.3 mL) under a nitrogen atmosphere. The mixture was stirred for 1 hour in a balloon filled with hydrogen, filtered, and the filtrate was taken to dryness. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate, dissolved in diethyl ether, and washed with 2 N hydrochloric acid (10 mL) and 10% sodium bicarbonate, dried over sodium sulfate, and concentrated to give cis-[3-(3-hydroxypropenyl)phenoxy]acetic acid tert-butyl ester as a colorless oil (420 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCN4CCCC4)c(F)cc(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
709 mg (1.35 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.14 mL (13.5 mmol) of pyrrolidine and 1.86 g (13.5 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 8 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:9:1) to give 431 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(pyrrolidin-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:22])([CH3:21])[CH2:16][CH:17]([C:18](O)=[O:19])[C:11]2=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:22])([CH3:21])[CH2:16][CH:17]([C:18]([NH:33][CH2:32][CH2:30][OH:31])=[O:19])[C:11]2=[CH:10][C:9]=1[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1
Reactant: NCCO
Reactant: CC1(C)CC(C(=O)O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Product: CC1(C)CC(C(=O)NCCO)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1

Procedure:
Using the product of Step B and ethanolamine, along with the procedure described in Example 88, the title compound was afforded. Further separation on an AS chiral column, eluting with 7% EtOH/heptane, afforded the enantiomers: (LC-2) HPLC/MS (fast isomer on AS): 471.3 (M+1), 473.3 (M+3); Rt=3.13 min. (LC-2) HPLC/MS (slow isomer on AS): 471.3 (M+1), 473.3 (M+3); Rt=3.13 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][CH:3]=1.[C-:10]#[N:11].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:10]#[N:11])[CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCc1cccc(Br)n1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a stirred solution of the above crude 6-bromo-2-bromomethylpyridine (70 g, 0.28 mol) in dioxane (500 mL) and water (250 mL), was added NaCN (28 g, 0.74 mol) at 0° C. and then stirred at RT for 16 h. The reaction mixture was quenched with 3 Lit of water and extracted with ethylacetate (4×500 mL). The organic layer was washed with water (400 L), brine (250 mL), dried over Na2SO4 and concentrated to give crude product. The crude was purified by column chromatography over silica gel (pet. ether/ethylacetate, 8:2) to give 6-bromopyridine-2-yl-acetonitrile (22.5 g, 40%). [TLC: Pet. ether/ethylacetate, 7:3, Rf=0.35]
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([C:18]([OH:20])=O)=[C:4]1[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:5]1=[N:6]2.[CH3:21][N:22]([CH3:27])[CH2:23][CH:24]([NH2:26])C.[CH2:28](N(CC)CC)C>O=S(Cl)Cl.C(Cl)Cl>[CH3:21][N:22]([CH3:27])[CH:23]([CH3:28])[CH2:24][NH:26][C:18]([C:3]1[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=2)[N:6]=[C:5]2[C:11]3[C:16]([NH:17][C:4]=12)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:20]
Reactant: O=C(O)c1c2ccccc2nc2c1[nH]c1ccccc12
Reactant: CCN(CC)CC
Reactant: CC(N)CN(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(CNC(=O)c1c2ccccc2nc2c1[nH]c1ccccc12)N(C)C
Reaction time: 14 h
Yield: 31 %

Procedure:
10H-Indolo[3,2-b]quinoline-11-carboxylic acid (0.2 g, 0.76 mmol) was dissolved in 8 ml of refluxing SOCl2. After 6 hours a clear solution was obtained, and all volatiles were removed in vacuo. The crude acid chloride was suspended in 10 ml of CH2Cl2. A solution of N,N-dimethylproylendiamine (0.1 mL, 0.97 mmol) and triethylamine (1 ml) in 10 ml of CH2Cl2 was added at room temperature, and the mixture was stirred for 14 hours. The organic phase was washed (NaHCO3, brine) and dried (MgSO4). Removal of the solvent and purification by chromatography on alumina (CH2Cl2/MeOH, 90:10) yielded the desired compound (80 mg, 31%) as a solid. m. p. 188-189° C. 1H-NMR [MeOD,_, ppm]: 8.16 (d, J=7.8 Hz, 1H), 7.92 (m, 2H), 7.35-7.20 (m, 3H), 7.04 (m, 2H), 3.62 (m, 2H, CH2NO), 2.55 (m, 2H, CH2N(CH3)2), 2.29 (s, 6H, N(CH3)2), 1.88 (m, 2H, CHO. MS (EI, m/z) 347 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C@@H:6]1[CH2:19][CH2:20][C:21](=[O:23])[CH2:22][C@H:5]21.CC(C)([O-])C.[K+].[CH3:30][O:31][CH2:32]Cl.C1[CH2:38][O:37][CH2:36]C1>>[CH3:30][O:31][CH2:32][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:36][O:37][CH3:38])=[CH:16][CH:17]=1)[CH:6]1[CH2:19][CH2:20][C:21](=[O:23])[CH2:22][CH:5]21
Reactant: C1CCOC1
Reactant: COCCl
Reactant: O=C1CC[C@@H]2[C@H](C1)c1cc(O)ccc1O[C@@H]2c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(=O)CCC32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0 C solution of Example 19 (0.100 g, 0.32 mmol) in THF (3 mL) add potassium tert-butoxide (0.090 g, 0.81 mmol) followed by methoxymethyl chloride (MOM-CI) (0.061 mL, 0.81 mmol). Remove the ice bath and stir for 1 h at room temperature. Pour the contents into ½ satd. NaHCO3 (50 mL) and extract with Et2O (2×25 mL) and EtOAc (2×25 mL). Wash the combine organic extracts with brine (50 mL.), dry over Na2SO4, and concentrate to afford a brown residue. Purify the residue by MPLC (0% to 25% to 50% EtOAchexanes) to afford Preparation 35 (0.102 g, 80%). 1H NMR (CDCl3) δ 7.37 (d, J=8.4 Hz, 2 H), 7.09 (d, J=8.4 Hz, 2 H), 6.96 (d, J=2.4 Hz, 1 H), 6.87 (dd, J=2.4, 8.8 Hz, 1 H), 6.84 (d, J=8.8 Hz, 1 H), 5.28 (s, 1 H), 5.20 (s, 2 H), 5.13 (A of AB, JAB=7.0 Hz, 1 H), 5.07 (B of AB, JAB=7.0 Hz, 1 H), 3.87 (m, 1 H), 3.50 (s, 3 H), 3.48 (s, 3 H), 3.04 (br d, J=14.4 Hz, 1 H), 2.79 (dd, J=6.2, 14.4 Hz, 1 H), 2.46 (m, 1 H), 2.21 (m, 2 H), 1.62-1.79 (m, 2 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH2:34][CH2:35][CH:36]([C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[OH:37]>>[OH:37][CH:36]([C:38]1[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: NCC(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc([N+](=O)[O-])cc2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtained in 72% purity by HPLC. MS(ESI+): m/z=504.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1.[CH3:16][O:17]C(Cl)Cl.Cl>C(Cl)Cl>[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[CH:16]=[O:17]
Reactant: COC(Cl)Cl
Reactant: Cc1cc2ccccc2s1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1sc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
SnCl4 (20 mL, 67 mmole) was added over 5 min to a stirred solution of 2-methylbenzo[b]thiophene (5.0 g, 33.7 mmole) in CH2Cl2 (75 mL) at 0° C. under argon. After 15 minutes, dichloromethyl methyl ether (3.7 mL, 41 mmole) was added. The reaction became a yellowish colored suspension. The reaction was allowed to warm to RT and stirred for 16 h, then was poured onto ice water (200 mL). The aqueous mixture was acidified with 1.0 N HCl (100 mL) and stirred until the suspension dissolved. The organic phase was separated, dried (MgSO4), and concentrated under vacuum. Purification by flash chromatography on silica gel (10% ethyl acetate/hexane) gave the title compound (5.83 g, 98%) as a white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1 H), 8.61 (d, J=8.1 Hz, 1 H), 7.77 (d, J=8.0 Hz, 1 H), 7.48 (t, 1 H), 7.39 (t, 1 H), 2.93 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:3]=1[NH:4][S:5]([CH3:8])(=[O:7])=[O:6].C(N(CC)CC)C.[F:23][S:24]([C:27]1[CH:28]=C(S(Cl)(=O)=O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>O1CCCC1>[NH2:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:3]=1[N:4]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[S:5]([C:8]1[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([F:23])(=[O:25])=[O:26])[CH:28]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(F)c1cccc(S(=O)(=O)Cl)c1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NN(c1ccc([N+](=O)[O-])cc1N)S(=O)(=O)c1cccc(S(=O)(=O)F)c1
Temperature: 5 °C
Yield: 166.2 %

Procedure:
2'-Amino-4'-nitromethanesulfonanilide (30.4 g; 0.13 mole) was dissolved in dry tetrahydrofuran (ca. 700 ml) and then triethylamine (13.1 g; 0.13 mole) was added and the solution was chilled to 5° C. While stirring and maintaining a temperature <10° C., While stirring and maintaining a temperature <10° C., m-fluorosulfonylbenzenesulfonyl chloride (33.8 g; 0.13 mole) was added dropwise. After the addition, the reaction was kept at the ice bath temperature for one hour and then stirring continued at room temperature for an additional hour. The reaction solution was poured into ice cold water (about 2 liters) while stirring and scratching vigorously. The product was filtered and dried to yield 50.6 g (85 percent) beige solid, m.p. 204° to 209° C. A small sample (1 g) was recrystallized from ethanol (150 ml) to yield a beige solid, m.p. 224° to 226° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:27])[C:19]([O:21][CH2:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:28])[NH:6]2.C1C=C(Cl)C=C(C(OO)=[O:37])C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:27])[C:19]([O:21][CH2:22][CH2:23][CH2:24][S:25]([CH3:26])=[O:37])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:28])[NH:6]2
Reactant: CSCCCOc1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCCCS(C)=O)c(C)c34)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a solution of Example 29 (25 mg, 0.0625 mmol) in dichloromethane at 0° C. was added m-CPBA (77%, 14 mg, 0.0625 mmol). After stirring the mixture at 0° C. for 30 min, triphenylphosphine (5 mg, 0.019 mmol) was added. After stirring at 0° C. for additional 30 min, the reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to afford the title compound (11 mg, 42% yield) as a white solid. MS: (M+H)+=417.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C([OH:18])(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-:18])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)O
Reactant: Clc1ccccc1Oc1cccnc1
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2ccccc2Cl)c1

Procedure:
A solution of 74.3 g of 3-(2-chlorophenoxy)pyridine [Agr. Biol. Ghem., 34, 68 (1970)] in 75 ml of glacial acetic acid in three equal portions. The temperature is maintained at 35°-40° C. for 16 hours and 75 ml of isopropanol is added and the mixture is refluxed 1 hour. The mixture is concentrated at reduced pressure and the oil is dissolved in 500 ml of dichloromethane. The extract is washed with 25% sodium hydroxide solution, concentrated and distilled to yield 3-(2-chlorophenoxy)pyridine 1-oxide, bp 145°-160° C. at 0.15 mM, mp 60°-64° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.103) (0.24 g, 0.68 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.28 g, 0.81 mmol) according to the general procedure VI. Obtained as light brown solid (0.27 g), which was subsequently deprotected.
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])[CH3:11].O>CO>[CH:10]([N:13]=[N:14][C:15]1([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N=NC1(Oc2ccccc2)CCCCC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5.95 grams (0.09 moles) of 85% potassium hydroxide in 50 mls of methanol in a 125 ml erlenmeyer flask was added 8.46 grams (0.09 moles) of phenol and the solution stirred for 15 minutes. The solution was cooled to 20° C. and 15.0 grams (0.08 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise over 5 minutes and the reaction mixture stirred an additional hour at 20°-25° C. The reaction mixture was poured into 300 mls water and the product extracted with 200 mls of pentane. The pentane solution was separated and washed successively with 100 ml portions of 10% sodium hydroxide, water, 10% HCl (twice), 15% HCl, water, 15% sodium bisulfite solution and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and it weighed 15.7 grams (76.5% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-phenoxycyclohexane. Gas chromatography indicated there was also a small amount of 1-isopropylazo-1-methoxycyclohexane from a competing reaction of the methanol with the 1-isopropylazo-1-chlorocyclohexane.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:14]([CH3:13])[O:15][CH3:16])=[O:6]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: CNOC
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.1 %

Procedure:
To a solution of 3-bromo-2-methyl benzoic acid (430 mg, 2.00 mmol) in anhydrous DCM, under nitrogen at ambient temperature was added N,O-dimethylhydroxylamine hydrochloride (215 mg, 2.20 mmol), pyridine (0.18 mL, 2.23 mmol) and CBr4 (662 mg, 2.00 mmol). Triphenyl phosphine (576 mg, 2.20 mmol) was added portion-wise over 10 min and the resulting mixture stirred at ambient temperature for 2.5 h. The reaction mixture then reduced under vacuum and purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 4:1) to afford the title compound as a colourless oil (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:15])O[C:12](=[O:14])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[NH:22]([N:23]1[C:12](=[O:14])[CH:13]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]1=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1C=C(c2ccc(Cl)c(Cl)c2)C(=O)O1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: O=C1C=C(c2ccc(Cl)c(Cl)c2)C(=O)N1Nc1ccccc1

Procedure:
2.43 g (10 mmol) of -(3,4-dichlorophenyl)furan-2,5-dione and 1.08 g (10 mmol) of phenyl hydrazine in 50 ml of glacial acetic acid were boiled under ref lux for 5 h. The mixture was cooled and the product was then filtered off and washed first with glacial acetic acid and subquently with pentane. Yield: 1.8 g of a crystalline solid, m.p. 208-210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH:34]1(C=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH:34]1([CH2:27][N:24]2[CH2:23][CH2:22][CH:21]([N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:10](=[O:20])[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=CC1CCCCC1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(CC3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). Cyclohexanecarboxaldehyde (0.138 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 17 mg; HRMS (FAB+, NBA) (M+H)+ 449.3163, C29H41N2O2 requires 449.3168; LC-MS: (M+H)+ 449.2, tr 7.92 min.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[CH:25]([OH:26])[C:24]4[CH:27]=[CH:28][CH:29]=[C:22]5[C:23]=4[C:18](=[CH:19][CH:20]=[CH:21]5)[C:17]3=[O:30])[CH2:10][CH2:9]2)C=C[CH:4]=[CH:3][CH:2]=1.[N:31]1C=CC=CC=1N1CCNCC1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[N:31]1[CH:4]=[CH:3][CH:2]=[CH:1][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:17](=[O:30])[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:23]=3[C:24](=[CH:27][CH:28]=[CH:29]4)[C:25]2=[O:26])[CH2:12][CH2:13]1
Reactant: O=C1c2cccc3cccc(c23)C(O)N1CCN1CCN(Cc2ccccc2)CC1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCN1CCN(c2ccccn2)CC1

Procedure:
10 g. (0.025 moles) of the ester from example 1 (b), 4.1 g. (0.025 moles) of 1-(2-pyridinyl)piperazine and 3.27 g. (0.0253 moles) of diisopropylethylamine are refluxed in 300 ml. of toluene for 3.5 hours. The toluene is evaporated and the residue is dissolved in chloroform and washed with water (all aqueous layers are backwashed). The chloroform is evaporated and the residue is recrystallized from chloroform/ethanol to yield 2-[2-[4-(2-pyridyl)-1-piperazinyl]ethyl]-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 188°-190°.