Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@H:3]1[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[CH2:15][NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](CNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CNCC[C@@H]1O)OCc1ccccc1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a flask containing 1,1-dimethylethyl (3R,4S)-4-hydroxy-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (for a preparation see Example 135(e)) (1 g; 2.74 mmol) was added 100 mL of TFA/DCM (50%). The reaction mixture was stirred for 1 h and then concentrated. The crude product was made basic by the addition of 6N NaOH and extracted into 10% MeOH/DCM (2×50 mL). The organic fractions were dried with anhydrous sodium sulfate, filtered and concentrated to obtain the product as a clear oil (607 mg; 84%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH3:20])[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:24][CH3:23])[C:12]=2[O:19][CH3:20])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1cc(Br)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Br)ccc2C#N)c1OC
Yield: 69.3 %

Procedure:
4-Bromo-2-(3-formyl-2-methoxyphenoxy)benzonitrile (0.55 g, 1.7 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (120 mg, 1.9 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (40 mL) for 17 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.20 g, 1.7 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-bromo-2-(2-methoxy-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (546 mg, 71%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([O-])([O-])=O.[K+].[K+].IC>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3-methyl-phenol (500 mg, 2.67 mmol, 1 eq.) in acetonitrile (5 mL) is added K2CO3 (1.47 g, 10.6 mmol, 4 eq.). The mixture is stirred for 30 minutes at room temperature. Iodomethane (493 mg, 1.3 eq) is then added dropwise via syringe and the mixture is stirred for 12 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel column chromatography (5% EtOAc in hexanes) to give 1-Bromo-4-methoxy-2-methyl-benzene.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[NH2:12][C@@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[C:31]([O:33][CH3:34])=[O:32])[C@H:23]2[C@H:14]1[C@:15]1([CH3:36])[C@H:20]([CH2:21][CH2:22]2)[CH2:19][C@H:18]([OH:35])[CH2:17][CH2:16]1>C(O)C.C([O-])(O)=O.[Na+]>[CH:1]1([NH:12][C@@H:13]2[CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][CH2:26][C@@H:27]3[C:31]([O:33][CH3:34])=[O:32])[C@H:23]3[C@H:14]2[C@:15]2([CH3:36])[C@H:20]([CH2:21][CH2:22]3)[CH2:19][C@H:18]([OH:35])[CH2:17][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C

Procedure:
Cyclohexanone (2.9 ml) and sodium cyanoborohydride (2.512 g) were added to a stirred solution of methyl 11α-amino-3α-hydroxy-5β-androstane-17β-carboxylate (2.505 g) in ethanol (30 ml). After 5 h the mixture was diluted with 5% NaHCO3 solution and extracted with ether (×2). The extract was washed with water (×2), dried Na2SO4) and evaporated to leave a froth (2.544 g). A sample (0.39 g) was purified by preparative t.l.c. using CHCl3 :MeOH (19:1) to give the title compound [α]D -9°, νmax 1725 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:3]=1.[C:18](Cl)(=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>ClCCl>[Cl:11][C:10]1[C:2]([NH:1][C:18]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:25])=[CH:3][C:4]([O:12][CH:13]([CH3:17])[C:14]#[C:15][CH3:16])=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: CC#CC(C)Oc1cc(N)c(Cl)cc1C(N)=O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC#CC(C)Oc1cc(NC(=O)OCC(Cl)(Cl)Cl)c(Cl)cc1C(N)=O

Procedure:
0.75 g of (S)-N-(8-methyl-8-azabicyclo 3.2.1!oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide, 0.51 g of 2,2,2-trichloroethyl chlorocarbonate and 0.41 g of potassium carbonate were added to toluene. The obtained mixture was refluxed for 3 hours and cooled, followed by the addition thereto of dichloromethane. The resulting mixture was washed with 1N hydrochloric acid, dried over magnesium sulfate, and freed from the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane (1:4) mixture) to give 0.50 g of (S)-N-(8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo 3.2.1!oct-3α-yl)-5-chloro-2-(1-methyl-2-butynyl)oxy-4-(2,2,2-trichloroethoxycarbonylamino)benzamide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16]C(=O)C)=[CH:10][C:8]=2[CH:9]=1)=[O:4].[CH3:20][NH:21][CH:22](O)[CH3:23].C(=O)([O-])[O-:26].[K+].[K+].O>CC(C)=O>[OH:16][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]2[O:6][C:5]([C:3]3([OH:4])[O:26][CH2:23][CH2:22][N:21]([CH3:20])[CH2:2]3)=[CH:9][C:8]=2[CH:10]=1
Reactant: CNC(C)O
Reactant: CC(=O)Oc1cc2cc(C(=O)CBr)oc2c(C)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(O)cc2cc(C3(O)CN(C)CCO3)oc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 2-bromo-1-(5-acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone (30 mg), methylaminoethanol (7 mg), and potassium carbonate (20 mg) in acetone (10 mL) was stirred at RT for 1 h. The mixture was poured into water and extracted with ethylacetate. The organic layer was dried and evaporated followed by purification by silica gel column chromatography eluting with 5% MeOH in DCM to give 20 mg of 2-(5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-4-methyl-morpholin-2-ol as an oil, and was converted into the HCl salt. The NMR showed an equilibrium of the hemiketal and ketone form. 1H NMR (CDCl3, 300 MHz) δ: 7.51, 7.26 (2s, combined, 1 H), 7.06, 6.87 (2s, combined 1H), 4.2–3.7 (m, 2H), 3.2–2.8 (m, 4H), 2.5–2.0 (m, 12 H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 189.26, 170.43, 170.18, 156.79, 152.53, 145.71, 125.79, 125.39, 124.46, 121.73, 113.88, 113.14, 111.52, 104.28, 92.48, 63.55, 62.62, 61.11, 59.68, 54.75, 46.37, 21.30, 13.48, 13.02, 12.90 ppm. M/S 320 (M+H+).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][CH2:10][CH:11]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=1[Cl:25])[CH3:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:14]=1[NH:13][CH:11]([CH3:12])[CH2:10][O:9][CH2:8][C:6]([OH:7])=[O:5])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1ccc(NC(C)COCC(=O)OC(C)(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NC(C)COCC(=O)O)c(Cl)c1

Procedure:
Prepared analogously to Example 1g from ethyl 4-[2-(tert.-butoxycarbonyl-methoxy)-1-methyl-ethylamino]-3-chloro-benzoate and trifluoroacetic acid in dichloromethane.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:36]1([OH:40])[CH2:39][CH2:38][CH2:37]1>>[CH:36]1([O:40][C:2]2[N:7]=[CH:6][C:5]([C:8]3([OH:35])[CH2:13][CH2:12][CH:11]([N:14]4[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=5)=[O:20])[CH2:17]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: OC1CCC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(OC4CCC4)nc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 6a and cyclobutanol (Aldrich) using the procedure described in Example 8.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@:5]([CH3:39])([C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=O)[CH2:4][O:3]1.[OH2:41].C1(C)C=CC([S:48](O)(=O)=[O:49])=CC=1>CO>[NH2:6][C@@:5]([C:14]1[S:48][C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=[N:17][N:16]=1)([CH3:39])[CH2:4][OH:3].[C:21]([OH:49])([C:34]([F:37])([F:36])[F:35])=[O:41]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: CO
Product: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)CO)s2)cc1C(F)(F)F
Product: O=C(O)C(F)(F)F
Yield: 155.9 %

Procedure:
A solution of (S)-tert-butyl 2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate (D9) (156 mg, 0.27 mmol) in methanol (10 mL) was treated with p-toluenesulfonic acid monohydrate (259 mg, 1.36 mmol) at 70° C. for 3 hours. Two thirds of the reaction mixture was then purified by prep HPLC on a C8(2) column ((Luna, 5μ, 100×21.10 mm) with acetonitrile-H2O (0.1% TFA) as mobile phase and gradient 30-98% in 20 min. The title compound was obtained as the bis-TFA salt (24 mg). MS (ESI): 432.00 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 8.21 (dd, 1H, J=2.0 Hz, J=8.8 Hz), 8.15 (d, 1H, J=2.0 Hz), 8.09 (br s, 2H), 7.45 (d, 1H, J=8.8 Hz), 5.96 (t, 1H, J=4.8 Hz), 4.21 (t, 2H, J=6.4 Hz), 3.81 (dd, 1H, J=11.2 Hz, J=5.2 Hz), 3.73 (dd, 1H, J=11.2 Hz, J=5.2 Hz), 1.76 (m, 2H), 1.66 (s, 3H), 1.44 (m, 2H), 1.28 (m, 8H), 0.86 (t, 3H, J=6.8 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25]=[C:26]=[O:27]>O1CCCC1>[CH3:24][NH:25][C:26](=[O:27])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH:9]=[CH:10]2
Reactant: CN=C=O
Reactant: Oc1ccc2c(ccn2Cc2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(ccn2Cc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-pyridinylmethyl)-1H-indol-5-ol (2.4 g) in 50 ml tetrahydrofuran, was added milled K2CO3 (1.5 g), followed by methyl isocyanate (0.65 ml). After stirring at ambient temperature for three hours, the mixture was filtered and the filtrate evaporated to a solid, 3.0 g, m.p. 170° C. This material was eluted on a silica gel column with 2% methanol/dichloromethane via high pressure liquid chromatography (HPLC) and the desired fractions were combined, then evaporated to yield 2.4 g of 1-(4-pyridinylmethyl)-1H-indol-5-yl methylcarbamate, as a solid, m.p. 179°-180° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[N+:17]([O-])([O-:19])=[O:18].[K+].O1C2C=CC=CC=2C=CC1>S(=O)(=O)(O)O>[N+:17]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][C:2]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:4]2=[O:11])([O-:19])=[O:18]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cc(=O)c2ccccc2o1
Agent: C1=Cc2ccccc2OC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cc(=O)c2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of ethyl chromone-2-carboxylate (Example 16) in about 3 mL of sulfuric acid cooled to −10° C. is added about 1 mL potassium nitrate in sulfuric acid. The molar ratio of potassium nitrate to the benzopyran is slightly greater than 1:1. The reaction mixture is stirred at 0° C. for 1 h, the ice bath removed, and the reaction stirred at room temperature until the reaction is complete by HPLC (<3% benzopyran): about 4-6 h. The nitrated benzopyran precipitates as the reaction progresses. The reaction mixture is poured onto ice, and the precipitate is dissolved in ethyl acetate. The ethyl acetate layer is dried, filtered, and evaporated to afford ethyl 6-nitrochromone-2-carboxylate as a light yellow solid (about 90% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:23]1[C:24]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:29][C:25]=2[N:26]=[CH:27][N:28]=1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:23]2[C:24]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Reaction time: 15 h
Yield: 68.5 %

Procedure:
After adding 123 mg of 4-nitrophenol, 136 mg of potassium carbonate and 1.5 ml of dimethylformamide to 113 mg of the 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266 and PCT/EP96/02728, and stirring the mixture for 15 hours at 130–135° C., and additional 60 mg of 4-nitrophenol and 75 mg of potassium carbonate were added and the mixture was stirred for 6 hours. After returning the mixture to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the solid obtained by concentration to dryness was washed with ether to obtain 112 mg of the title compound.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][Br:6])(=[O:4])=[O:3]
Reactant: O=C(Cl)CCCCBr
Reactant: CS(N)(=O)=O
Agent: C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCCCBr
Yield: 86 %

Procedure:
A mixture of 0.950 g (0.01 mole) of methanesulfonamide and 1.80 g. (0.01 mole) of 5-bromovaleric acid chloride was heated on a steam bath until gas evolution ceased (ca. 5 minutes). The brown reaction mixture was allowed to cool and was dissolved in methylene chloride. The methylene chloride solution was treated with Darco, was filtered, and was diluted with hexane with cooling to afford the white, crystalline N-methanesulfonyl-5-bromovaleramide weighing 2.22 g. (86.0% yield) which melted at 88°-89°.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25]CC)=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(Cl)cc2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-chloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (95 mg, 0.249 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (43 mg, 1.02 mmol). The reaction was heated to 60° C. for 4 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 45 as yellow solid (49 mg, 56%). ESI-MS m/z: 354 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.34 (d, J=7.2 Hz, 1H), 8.27 (s, 1H), 7.68-7.56 (m, 5H), 2.84 (s, 3H), 2.55-2.52 (m, 1H), 2.39 (s, 3H), 1.08-1.05 (m, 2H), 0.80-0.78 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[C:18]([Br:26])=[CH:19][CH:20]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:13]=3[C:12](=[O:27])[C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[BrH:26].[O:27]=[C:12]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:17][C:16]=2[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:13]1=2
Reactant: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Br
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Yield: 65.1 %

Procedure:
To a solution of methyl 2-benzyl-9-bromo-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (6.6 g, 15.4 mmol) in MeOH (100 mL) was added Pd/C (3.0 g, 5%, 50% water), the mixture was stirred at atmosphere of hydrogen for about 6.0 h. Then the mixture was filtered, washed with MeOH (20 mL). The filtrate was concentrated and the residue was recrystallized with MeOH (2.5 mL) to afford the product (3.4 g, 65%) as a white solid. 1H NMR (DMSO-d6) δ 12.0 (s, 1H), 9.18 (s, 1H), 7.61-7.72 (m, 2H), 7.22-7.23 (m, 1H), 4.32 (s, 2H), 3.81 (s, 3H), 3.38-3.40 (m, 2H), and 2.66-2.67 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.[C:10]([CH2:13][N:14]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][N:20]([CH2:26][C:27]([OH:29])=[O:28])[CH2:19][CH2:18][N:17]([CH2:30][C:31]([OH:33])=[O:32])[CH2:16][CH2:15]1)([OH:12])=[O:11].[OH-].[K+]>O1CCOCC1.O>[OH:4][CH:2]([CH2:1][O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][N:23]1[CH2:24][CH2:25][N:14]([CH2:13][C:10]([OH:12])=[O:11])[CH2:15][CH2:16][N:17]([CH2:30][C:31]([OH:33])=[O:32])[CH2:18][CH2:19][N:20]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OCC1CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OCC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
11.27 g (86.58 mmol) of glycidyl-tert-butyl ether and 10 g (28.86 mmol) of 1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6 N potassium hydroxide solution. It is stirred for 24 hours at 70° C. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl-methyl ether. The aqueous solution is adjusted to pH 1 with 5 N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent =gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.38 g (71% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:27]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH2:25][CH3:26])[CH:18]=2)[CH2:12][CH2:11]1)=[O:8].[C:28](Cl)(=[O:30])[CH3:29]>>[C:28]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:27]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH2:25][CH3:26])[CH:18]=2)[CH2:12][CH2:11]1)=[O:8])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cncc(N)c3)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(NC(C)=O)c3)CC2)ccc1Cl
Yield: 26 %

Procedure:
The title compound (12 mg, 26%) was prepared analogously to example 7 by coupling of 5-amino-N-[1-(4-chloro-3-ethoxy-benzyl)piperidin-4-yl]-nicotinamide with acetyl chloride. MS: 431.4 (MH+).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1cccnc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromo-3-methylpyridine
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]([N:12]([CH2:17][CH2:18][S:19][CH3:20])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]=2[O:5][C:4]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)#[N:2].[OH:31]S([O-])(=O)=O.[K+]>CO.O>[C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:21]3[CH2:23][CH2:22]3)[C:10]([N:12]([CH2:17][CH2:18][S:19]([CH3:20])=[O:31])[S:13]([CH3:16])(=[O:14])=[O:15])=[CH:11][C:6]=2[O:5][C:4]=1[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)#[N:2]
Reactant: CSCCN(c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1)S(C)(=O)=O
Reactant: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)CCN(c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of Example 12A (0.142 g, 0.320 mmol) in methanol (3 mL) cooled to 0-5° C. was slowly added dropwise a solution of 2 KHSO5.KHSO4.K2SO4 (0.216 g, 0.352 mmol) in water (1 mL). The reaction mixture was stirred for 10 minutes in the ice bath, then at room temperature for 22 hours. The reaction was incomplete by analytical LCMS so additional 2 KHSO5.KHSO4.K2SO4 (111 mg) was added in portions, followed by stirring at room temperature for 2.5 hours. Then more 2KHSO5.KHSO4.K2SO4 (245 mg) was added in portions followed by water (1 mL). The reaction mixture was heated at 50° C. for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and brine. The aqueous phase was further extracted with ethyl acetate (1×). The combined organic extracts were washed with water (2×), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a mixture of the title compounds (0.1436 g). MS (ESI+) m/z 494 (M+NH4)+ for sulfone; MS (ESI+) m/z 461 (M+H)+ for sulfoxide.