Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].[N:42]12[CH2:49]C[CH:45]([CH2:46][CH2:47]1)[C@@H:44](O)[CH2:43]2>C1(C)C=CC=CC=1.CC(O)C.CC(O)C.CC(O)C.CC(O)C.[Ti]>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][C@@H:38]1[CH:45]2[CH2:46][CH2:47][N:42]([CH2:43][CH2:44]2)[CH2:49]1)=[O:36]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=C(O[C@H]1CN2CCC1CC2)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Yield: 34 %

Procedure:
To a refluxing solution of methyl 3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.33 g, 0.59 mmol) and (R)-3-quinuclidinol (0.3 g, 2.4 mmol) in toluene (5 mL), was added titanium(IV)-i-propoxide (0.173 mL, 0.59 mmol, d=0.97). After refluxing for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound (0.13 g, 34%); 1H NMR (DMSO-d6): δ 1.31-1.34 (m, 1H), 1.51-1.55 (m, 4H), 1.78-1.88 (m, 3H), 1.98-2.01 (m, 1H), 2.33 (t, 2H, J=7.2 Hz), 2.52-2.72 (m, 11H), 3.15-3.21 (m, 1H), 3.85 (t, 2H, J=6.8 Hz), 4.59-4.62 (m, 4H), 4.90-4.92 (m, 1H), 6.76 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.24 (m, 3H), 7.52-7.59 (m, 2H), 7.87-7.92 (m, 2H), 10.80 (br, 1H); MS for C38H44N6O4 m/z 649.11 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]#N)=[CH:13][CH:12]=3)=[O:5])C.[OH-:22].[K+].[C:24](O)(=[O:26])C>C(O)CO.O>[CH3:1][O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]([O:26][CH3:24])=[O:22])=[CH:13][CH:12]=3)=[O:5]
Reactant: [OH-]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C#N)cc3c2c1C
Reactant: CC(=O)O
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: COC(=O)c1ccc2[nH]c3cnc(C(=O)OC)c(C)c3c2c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
2.81 g of 6-cyano-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is heated with 4.6 g of potassium hydroxide in 20 ml of ethylene glycol for 16 hours at 150° C. After cooling to 0° C., 10 ml of acetic acid is added dropwise. The mixture is diluted with 100 ml of water and, after saturation with sodium chloride, is extracted with ethyl acetate. The extracts are washed until neutral with saturated common salt solution, dried using sodium sulphate, filtered, and the solvent is distilled off in vacuo. The crude product is dissolved in 30 ml of 10% methanolic hydrochloric acid and boiled for 5 hours under reflux. After distilling off the solvent in vacuo, 20 ml of dilute aqueous ammonia are added and the mixture is extracted with ethyl acetate. After washing until neutral, drying and distilling off the solvent, the crude product is recrystallized from diisopropyl ether. 1.36 g of 4-methyl-β-carbolin-3,6-dicarboxylic acid dimethyl ester of melting point 199°-204° C. is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10](Cl)[CH:9]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[N:19]1([CH2:18][CH2:17][O:14][C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
15.4 g (111.00 mmol) of potassium carbonate was added to a solution of 4.0 g (27.86 mmol) of 4-amino-2-chlorophenol and 5.1 g (27.86 mmol) of 1-(2-chloro-ethyl)-piperidine in 50 mL acetonitrile and the mixture was stirred for 48 hours at RT. The solvent was evaporated off i. vac., the residue was combined with water and the aqueous phase was exhaustively extracted with EtOAc. The combined org. extracts were washed with water, dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane/MeOH/conc. aqueous ammonia 90:10:1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:18])=[C:9]([NH:11]C(=O)C(F)(F)F)[CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[NH2:11][C:9]1[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[CH3:18]
Reactant: CC(=O)Nc1ccc(C)c(NC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(C)c(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(5-Acetylamino-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (2.93 g, 11.24 mmol) was taken up in methanol (50 mL) and sodium carbonate (5.96 g, 56.20 mmol) was added. The reaction was stirred at room temp for 12 h. The reaction mixture was into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was utilized without further purification. Yield 1.60 g. 1H NMR (CDCl3, 300 MHz): 82.16 (s, 3H). 2.31 (s, 3H), 7.18 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 7.64 (s, 1H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.C(OC([N:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)=O)(C)(C)C>ClCCl>[Br:13][C:9]1[N:8]=[C:7]([C:29]2[CH2:30][CH2:31][C:24]3([CH2:25][CH2:26][NH:21][CH2:22][CH2:23]3)[CH2:27][CH:28]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: ClCCl
Product: Brc1cccc(C2=CCC3(CCNCC3)CC2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Was prepared according to method A with the following variation: n-BuLi (1.6 M in hexanes (1.93 mL, 4.82 mmol)) was added drop-wise to a solution of 2,6-dibromopyridine (1.06 g, 4.48 mmol) in dichloromethane (25 mL). The reaction was stirred −78° C. for 30 min. 9-Oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (300 mg, 1.12 mmol) in dichloromethane (5 mL) was added drop-wise and the mixture was stirred at −78° C. for 1 h. White solid. Mp. 161.3-162.8° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][NH:30][CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:34])[N:19]=2)[CH2:14][CH2:13]1>>[NH2:34][C:20]1[N:21]=[C:22]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])[CH2:31]3)=[CH:26][CH:25]=2)[CH:23]=[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]2)[N:19]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from phenyl isocyanate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 5. Analytic LCMS (M+H)+: m/z=444.4.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Br:1][C:15]1[CH:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=[CH:11][C:10]=1[OH:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(O)c(Br)c1
Reaction time: 0.25 h

Procedure:
A solution of 9.4 g (52.8 mmoles) of N-bromosuccinimide in 450 mL of chloroform was added dropwise to a suspension 10 g (47.8 mmoles) of tert.butyl N-(4-hydroxy-phenyl)carbamate in 100 mL of chloroform at 0° C. over a period of 2 hours. The reaction mixture was stirred for an additional 15 min and then washed twice with water (first with 400 mL, then with 200 mL), dried over magnesium sulfate, filtered and partly evaporated. Hexane was added to the residue with stirring which caused the formation of a precipitate. The precipitate was filtered off and washed with hexane.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=3[N:18]=2)=[CH:10][CH:9]1[CH3:24])=[O:7])(C)(C)C.[O:25]1[CH2:27][C@H:26]1[CH2:28][O:29][C:30]1[C:38]2[CH:37]=[CH:36][O:35][C:34]=2[CH:33]=[CH:32][CH:31]=1.C[OH:40]>>[C:36]([OH:35])(=[O:40])[C:6]([OH:5])=[O:7].[O:35]1[CH:36]=[CH:37][C:38]2[C:30]([O:29][CH2:28][C@@H:26]([OH:25])[CH2:27][N:8]3[CH2:13][CH2:12][C@@H:11]([C:14]4[S:15][C:16]5[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=5[N:18]=4)[CH2:10][C@@H:9]3[CH3:24])=[CH:31][CH:32]=[CH:33][C:34]1=2
Reactant: Cc1cccc2sc(C3=CC(C)N(C(=O)OC(C)(C)C)CC3)nc12
Reactant: c1cc(OC[C@@H]2CO2)c2ccoc2c1
Reactant: CO
Product: Cc1cccc2sc([C@@H]3CCN(C[C@H](O)COc4cccc5occc45)[C@@H](C)C3)nc12
Product: O=C(O)C(=O)O

Procedure:
A solution of trans-4-(4-methylbenzothiazol-2-yl)-2-methylpiperidine (0.061 g, 0.248 mmol, prepared in example 24) and (S)-(+)-4-(oxiranylmethoxy)benzo[b]furan (0.047 g, 0.248 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/2% methanol/0.2% ammonium hydroxide in dichloromethane gradient elution) to give the free bases of the title compounds as two separate yellow oils. The oxalate salts were prepared to give the title compounds.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(N(C(C)C)CC)(C)C.ClCCl>C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:14][CH:13]=[CH2:12])=[O:8])=[CH:10][CH:11]=1
Reactant: C=CCBr
Reactant: O=C(O)c1ccc(CO)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)c1ccc(CO)cc1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of 4-hydroxymethylbenzoic acid (0.5 g, 3.3 mmol) in CHCl3 (10 mL) was added allyl bromide (0.6 mL, 0.84 g, 6.9 mmol) and diisopropylethylamine (1.3 mL, 0.96 g, 7.5 mmol). The resulting reaction mixture was allowed to reflux under nitrogen for 2.5 h. Upon cooling to rt, dichloromethane (50 mL) was added and the organic layer was washed with 0.1 N HCl (3×30 mL), 5% NaHCO3 solution (1×30 mL) and brine (1×30 mL). Upon drying (MgSO4), filtration of the drying agent and concentration, the resulting oily residue was chromatographed on silica gel (30% ethyl acetate/hexane) to give 440 mg (70%) of a colorless oil. 1H NMR (CDCl3) 8.06 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 6.11-5.98 (m, 11H), 5.42 (dd, J=17.2, 1.5 Hz, 11H), 5.30 (dd, J=10.4, 1.2 Hz, 1H), 4.83 (dd, J=5.6, 1.2 Hz, 2H), 4.78 (s, 2H), 1.80 (br s, 1H). MS 192 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([F:14])([CH3:13])[CH:7]([OH:12])[C:8]([O:10][CH3:11])=[O:9].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.O>CN(C)C=O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([F:14])([CH3:13])[CH:7]([O:12][C:21]1[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(O)C(C)(F)c1cccs1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(F)c1cccs1
Reaction time: 1 h

Procedure:
2.2 g (10 mmol) of methyl 3-(2-thienyl)-3-fluoro-2-hydroxybutyrate (Compound 1.1) are dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride is added. The mixture is stirred for 1 hour, and 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are then added. After the mixture has been stirred at room temperature for 24 hours, it is hydrolyzed using 10 ml of water, the pH is brought to 5 using acetic acid, and the solvent is distilled off under a high vacuum. The residue is taken up in ethyl acetate, washed with water and dried over sodium sulfate, and the solvent is distilled off. The residue is treated with 10 ml of methyl t-butyl ether and the precipitate formed filtered off with suction. After drying, 1.8 g of a white powder remain.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:14]1[O:16][CH:15]1[CH2:17][OH:18]>[Cr]>[OH:16][CH:15]([CH2:17][OH:18])[CH2:14][O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:18])=[O:12]
Reactant: O=C(O)CCCCCCCC(=O)O
Reactant: OCC1CO1
Agent: [Cr]
Product: O=C(CCCCCCCC(=O)OCC(O)CO)OCC(O)CO
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Azelaic acid 94 parts, 0.5 mol.) was heated to 120° C. A catalyst, AMC-2 (commercial chromium salt, 0.8 g) was added. Glycidol (81.5 g, 1.1 mol.) was added dropwise with stirring during 1 hour while keeping the temperature within 115° and 125° C. To complete the reaction, heating at 120° C. was continued for another hour. The product was a viscous liquid which crystallized very slowly to a waxy solid. It had residual acid and epoxy contents of 0.03 and 0.07 meq./g, respectively, and a purity of about 95%; 2,3-dihydroxypropyl groups per molecule: 2; molecular weight; 336.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C(Cl)(Cl)Cl.CO>[Si:30]([O:14][CH2:13][C@H:12]1[O:15][C@@H:8]([N:7]2[CH:16]=[C:3]([C:2]([F:1])([F:19])[F:20])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9][C@@H:10]1[OH:11])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 10 h
Yield: 40.6 %

Procedure:
A 1.0 g quantity of 5-trifluoromethyl-2'-deoxyuridine (3.6 mmoles) was dissolved in 3 ml of N,N-dimethylformamide. To the solution were added 0.49 g (7.2 mmoles) of imidazole and 0.64 g (4.3 mmoles) of tertbutyldimethylsilyl chloride, and the reaction was conducted at room temperature for 10 hours. The reaction mixture was treated in the same manner as in Example 1 with the exception of using chloroform/methanol (30:1) as an eluent for silica gel column chromatography, giving 0.6 g of the title compound as white crystals having a melting point of 199° to 200° C. Yield: 41%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.N#[O+:18]>C(#N)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:18])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#[O+]
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: N#Cc1ccc(C(=O)O)cc1
Yield: 94.2 %

Procedure:
Acetonitrile (20 ml) and p-cyanobenzamide (2.92 g) were placed in a 100-ml three-neck flask disposed in an ice bath. After the solution was cooled, a solution of nitrosonium tetrafluoroborate (2.57 g) in acetonitrile (20 ml) was added dropwise to the solution over five minutes with stirring. When the addition was completed, the solution was further stirred until generation of gas was terminated. The solvent was removed through distillation under reduced pressure, and water (10 ml) was added to the residue. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.77 g of p-cyanobenzoic acid (yield 95%). High performance liquid chromatographic analysis revealed that the p-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].CN(C)C=O.[N-:16]=[N+:17]=[N-:18].[Na+]>O>[CH:1]([CH:3]([N:16]=[N+:17]=[N-:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CC(Cl)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(N=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 ml round bottom flask equipped with a stir bar, 4.0 g (26.2 mm) of vinylbenzyl chloride, and 10 ml of dimethylformamide (DMF) were added. To this solution 3.40 g (52.4 mm) of sodium azide was added and the reaction mixture was stirred at room temperature overnight, after which time 50 ml of deionized water were added to the solution. The resulting 4-vinyl benzyl azide was extracted from the reaction solution with ethyl ether. The product was confirmed by 1H NMR.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][NH:25][C:26]2[C:31]([CH3:32])=[C:30]([CH3:33])[N:29]=[C:28](Cl)[C:27]=2[N+:35]([O-:37])=[O:36])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]C1C=CC=CC=1>COCCOCCOC>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][NH:25][C:26]2[C:27]([N+:35]([O-:37])=[O:36])=[C:28]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:29]=[C:30]([CH3:33])[C:31]=2[CH3:32])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCC2CCN(Cc3ccccc3)CC2)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCC2CCN(Cc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
Sodium hydride (1.196 g of 60%, 29.9 mmol) was added to a solution of phenol (2.81 g, 29.9 mol) in diglyme (40 mL). The mixture was stirred for 15 minutes after the cessation of gas evolution. A solution of N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine (10.9 g, 27.2 mmol) in hot diglyme was added to the phenoxide mixture. The reaction mixture was heated at reflux for 1.5 hours, cooled to ambient temperature, and then concentrated to remove the diglyme (60° C. bath, 21 Pa). The residue was purified by column chromatography eluting first with 1% methanol in dichloromethane to elute residual diglyme and then with 5% methanol in dichloromethane to remove product. The fractions were concentrated to provide 5.91 g of N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine as an orange-brown oil which solidified on standing.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].C(O[C:13](=O)[N:14](C)[CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[CH:32]2)[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(C)(C)C>C(OCC)(=O)C>[ClH:7].[ClH:7].[ClH:7].[CH3:39][N:35]1[C:36]2[C:31](=[CH:30][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:17]([CH2:16][CH2:15][NH:14][CH3:13])[CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]1=[O:40]
Reactant: CN(CCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 4N-hydrogen chloride ethyl acetate solution(4.2 ml) was added to an ethyl acetate solution (30 ml) of methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (1.0 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was condensed under reduced pressure to give the title compound(1.0 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH2:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:11]([OH:13])=[O:18]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassium permanganate (25.5 g, 2.5 eq) in water (1 l) is heated to reflux for 6 hours then cooled down to ambient temperature. The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2×300 ml). The aqueous phase is acidified with an aqueous solution of concentrated hydrochloric acid (12N) then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml. The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[C@@H:9]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>ClCCl.O>[CH3:22][N:8]([C@H:9]([C:10]([N:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1)=[O:12])[C:13]([CH3:21])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C(C)(C)c1ccccc1
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H](C(=O)N1CCOCC1)C(C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.12 h

Procedure:
To a cooled (0°C., ice bath) solution of (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid (1.0 g, 3.30 mmol, WO 99/32509) and benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (1.46 g, 3.30 mmol) in anhydrous dichloromethane (5 ml) is added diisopropylethylamine (1.15 ml, 6.60 mmol) under an inert atmosphere. To this solution is added a solution of morpholine (0.313 ml, 3.60 mmol) in dichloromethane (2.5 ml). After stirring at 0° C. for 5-10 minutes, the cooling bath is removed, and the resulting reaction mixture is stirred at room temperature for 15-20 hours. The mixture is diluted with water, and the aqueous layer is extracted with ethyl acetate (3 times). The combined extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed (silica gel, flash column), to give a dark yellow oil. (0.943 g, 76%) MS [M+H] 377.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.F[B-](F)(F)F.[CH3:18][O+](C)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:18])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2cc(Br)ccc2n1

Procedure:
A mixture of 6-bromo-2-[1H]-quinolone (2.90 g) and trimethyloxoniumtetrafluoroborate (2.10 g) was stirred in dichloromethane (50 cm3) for 48 hours under nitrogen. Aqueous 10% sodium hydroxide (20 cm3) was added and the aqueous phase was extracted with dichloromethane (2×40 cm3). The dried (MgSO4) extracts were evaporated and the residue was crystallised from petroleum ether (b.p. 60°-80°) to yield the title compound, m.p. 90°-94°, (2.16 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([CH3:12])=[CH:4][C:3]=1[O:13][CH2:14][CH:15]1[O:17][CH2:16]1.[CH3:18][CH:19]([NH2:21])[CH3:20].[CH2:22]([OH:24])C>>[CH3:12][C:5]1[CH:4]=[C:3]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:21][CH:19]([CH3:20])[CH3:18])[C:2]2[NH:1][C:22](=[O:24])[NH:8][C:7]=2[C:6]=1[CH3:11]
Reactant: CCO
Reactant: Cc1cc(OCC2CO2)c(N)c([N+](=O)[O-])c1C
Reactant: CC(C)N
Product: Cc1cc(OCC(O)CNC(C)C)c2[nH]c(=O)[nH]c2c1C

Procedure:
The diamino compound used as intermediate is obtained by reacting 2-amino-4,5-dimethyl-1-(2,3-epoxypropoxy)-3-nitrobenzene (see Example 8) with 2-propylamine in boiling ethanol and subsequent catalytic hydrogenation.