Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([Br:13])[N:3]=1.[CH3:14][O-:15].[Na+].O>CO>[Br:13][C:4]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:15][CH3:14])[N:3]=1
Reactant: COc1cc([N+](=O)[O-])c(Br)nc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])c(Br)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 g of 2,6-dibromo-3-methoxy-5-nitropyridine (example E3) were dissolved in 550 ml of anhydrous methanol at 30-40° C. 4.6 g sodium methoxide dissolved in 30 ml anhydrous methanol were added to this solution. The reaction mixture was stirred for one hour at room temperature, poured into 700 ml of water and stored in the refrigerator overnight. The precipitate was filtered, washed with ice cold water and dried under vacuum to yield the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O.[C:15](O)(=O)C>N1C=CC=CC=1>[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:15].[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)O
Agent: CCCCOC(=O)c1cccnc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cccnc1
Reaction time: 12 h

Procedure:
An electrically heated tubular reactor with an inner diameter (i. d.) of 12 mm was filled with 15 ml (12 g) of catalyst from example 1. Over a period of 12 h, a mixture of 17.9 g butyl nicotinate, 32 g water and 125 g acetic acid was metered using a precision pump to the reactor operating at 410° C. From the reaction mixture, 8.9 g of 3-acetylpyridine, 0.9 g of pyridine and 1.3 g of butyl nicotinate were obtained. This corresponded to a yield of 73% 3-acetylpyridine at a butyl nicotinate conversion of 93% (selectivity 78%). The selectivity of pyridine formation was 11%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:24][CH2:23][CH3:25])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2C)c2cccc(F)c21
Yield: 85 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 2-iodopropane (0.20 mL, 2.00 mmol) to give the title compound (0.279 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH2:28][O:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:28][O:29][CH2:30][C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[O:32])[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C(COCc1cccc(Br)n1)N1CCOCC1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(COCC(=O)N4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.12 g, 0.41 mmol) and 4-{[(6-bromopyridin-2-yl)methoxy]acetyl}morpholine (0.13 g, 0.40 mmol) as the starting materials.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30])C1C=CC=CC=1.C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[Cl:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][CH2:16][C:12]2[N:11]([CH3:28])[C:10]([C:29]([OH:31])=[O:30])=[C:9]([OH:8])[C:14](=[O:15])[CH:13]=2)(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=1
Reactant: Cn1c(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cn1c(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c(O)c1C(=O)O
Yield: 52.7 %

Procedure:
6-[(3-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-05) (170.0 mg, 52.67%) was synthesized as an off white solid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-05) (400.0 mg, 0.866 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: NCCCN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCCCN3CCOCC3)nc21
Temperature: 125 °C
Reaction time: 0.03 h

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 1.00 g (6.90 mmol) of N-(3-aminopropyl)morpholine and 0.5 mL of dimethylformamide was heated with stirring in a 125° C. oil bath. After 2 minutes, solution was complete. After 1.5 hours, the excess amine and dimethylformamide were evaporated at reduced pressure and the residue was triturated with 5 mL of water. The gum was dissolved in 25 mL of ethyl acetate, and the solution was washed with 2×5 mL of water, dried (potassium carbonate), and concentrated. Upon dissolution in 5 mL of ether, crystals of pure product separated; wt 0.101 g; mp 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 142.6 mg (0.339 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1) and 35.6 mg (0.848 mmol) of LiOH--H2O in 12 ml of THF/water (4:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the hexane fraction extracted with 5% aqueous NaOH. The aqueous layers were combined and acidified with 1M HCl, and then extracted with EtOAc and Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.91 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.47 (2H, s), 7.23 (4H, q, J=8.1 Hz), 7.01 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.33 (2H, d, J=4.8 Hz), 1.30 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24]([C:29](=[O:31])[CH3:30])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([F:40])[CH:46]=3)[CH:25]=[C:24]([C:29](=[O:31])[CH3:30])[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(C)=O)c2)c1CCC(=O)OCC
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Yield: 92.8 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-acetyl-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (303 mg, 0.5 mmol), 3-fluoro-phenylboronic acid (140 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (326 mg, 1.0 mmol) to obtain 4-[3-[6-(5-acetyl-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (288 mg, 93%) as a colorless oil: ES(+)-HRMS m/e calcd for C37H45FO7 (M+Na)+ 643.3041. found 643.3039.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=O)[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:4][C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2.[CH2:54](Br)Br>C(Cl)Cl.C1COCC1.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl.C(Br)Br.[Zn].[Zn].Cl[Ti](Cl)(Cl)Cl>[S:1]1[C:5]([C@H:6]([O:32][Si:33]([C:46]([CH3:48])([CH3:47])[CH3:49])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:54])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:4][C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2
Reactant: BrCBr
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H](OC2CCCCO2)CC(=O)[C@@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)OC)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: 0 °C

Procedure:
(Z)-Methyl 7-((1R,2R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3-oxo-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (15a, limiting reagent) is dissolved in DCM (0.05 M) under a nitrogen atmosphere and cooled to 0° C. A solution consisting of zinc methylene dibromide titanium tetrachloride is prepared by combining zinc dust (2.3 g) in THF (40 mL) with methylene dibromide (0.81 mL) at −40° C. under a nitrogen atmosphere. To the suspension is slowly added TiCl4 (0.92 mL). Portions (2 mL) of the zinc methylene dibromide titanium tetrachloride solution are added until the reaction is complete as judged by TLC. Upon completion, the reaction mixture is diluted with ethyl acetate and filtered twice through a bed of Celite. The filtrate is washed with a saturated aqueous solution of sodium bicarbonate, then with a 50% aqueous solution of brine. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 17a.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:39]5[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=5)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(F)cc5)ccc4C3=O)cc2F)C1

Procedure:
Trifluoromethanesulfonic acid 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ester was reacted with 4-fluorophenylboronic acid by method O. The product with the molecular weight of 447.53 (C27H27F2N3O) was obtained in this way; MS (ESI): 448 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH2:22][N:23]([CH3:25])[CH3:24])=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9](S(C1C=CC=CC=1)(=O)=O)[CH:8]=[CH:7]2)[CH3:2].CCO.[OH-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:5]([CH2:22][N:23]([CH3:24])[CH3:25])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc2[nH]ccc2c1CN(C)C

Procedure:
{[5-Ethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine (655 mg, 1.831 mmol; Example 133) was added EtOH (5 ml) and 2 M NaOH (5 ml) and heated at 70 oC for 5 h. Water was added and white material precipitated. The mixture was extracted with DCM. The organic phase was extracted with 1 M HCl (3×20 ml). The aqueous phase was made alkaline (pH 9) using 2 M NaOH and extracted with DCM (3×50 ml). The combined organic layers were dried (MgSO4) and evaporated. Yield: 293 mg (74%); brown oil. MS (ESI+) for C13H18N2O m/z 219 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CO>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: C1COCCN1
Solvent: CO
Product: C=Cc1ccc(CN2CCOCC2)cc1
Yield: 86.4 %

Procedure:
20 ml (0.14 mol) of 4-vinylbenzylchloride and 25 ml (0.28 mol) of morpholine were refluxed in 150 ml of methanol for 3 h. The mixture was then concentrated in vacuo, and the resulting residue was partitioned between 1M hydrochloric acid and water [sic]. The acidic phase was washed with ether and then made alkaline with 2M sodium hydroxide solution. This aqueous phase was extracted with ether. This organic phase was dried and concentrated in vacuo, resulting in 24.6 g of the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:24])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:16]1[N:15]=[C:14]([C:11]2([OH:24])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C(F)(F)F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cccc(C(F)(F)F)n2)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 4′-hydroxy-6-trifluoromethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (450 mg, 1.30 mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid (5 mL). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was concentrated in vacuo to give yellow oil. The oil was dissolved in methylene chloride, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-trifluoromethyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol (320 mg, 100%) as a yellow oil; LRMS for C11H13F3N2O3 (M+H)+ at m/z=246. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O.CC(O)=O.C([O-])(O)=O.[Na+]>[Fe].CO>[NH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[NH:2][CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNc1ccc(C(=O)OC)cc1N
Temperature: 25 °C

Procedure:
Fe powder (3.4 g, 60 mmol) was added to a mixture of methyl 4-methylamino-3-nitrobenzoate (2.5 g, 12.0 mmol), AcOH (10 mL) and MeOH (100 mL) at reflux. The mixture was heated at reflux for 30 min and allowed to cool to rt. The pH was adjusted to ˜8 by addition of NaHCO3 (aq, sat) and the mixture was filtered through Celite. The filter cake was washed with EtOH and the combined filtrates were concentrated and the residue extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated to give the sub-title compound. Yield: 1.91 g (88%)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][C:7]=2[N:8]=1.S(Cl)(Cl)=O.[CH2:20]([O:22][C:23]([CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH3:21].C(N(CC)CC)C>ClCCl.O1CCCC1>[C:28]1([N:27]([CH2:26][CH2:25][C:23]([O:22][CH2:20][CH3:21])=[O:24])[C:13]([C:10]2[CH:11]=[CH:12][C:6]3[S:5][C:4]([CH2:3][O:2][CH3:1])=[N:8][C:7]=3[CH:9]=2)=[O:15])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: COCc1nc2cc(C(=O)O)ccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(COC)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1.6 g (7.2 mmol) of 2-methoxymethylbenzothiazole-5-carboxylic acid in 60 mL dichloromethane was mixed with 1.6 mL (22 mmol) of thionyl chloride and refluxed for 1 hour. The solid dissolved after 20 minutes. After distillation of the liquid components, the crude product was taken up in dichloromethane twice more and each time the solvent was distilled off. The crude acid chloride thus obtained was taken up in 50 mL of tetrahydrofuran, added dropwise to a mixture of 1.4 g (7.2 mmol) of N-(2-ethoxycarbonylethyl)aniline and 3.0 mL (21 mmol) of triethylamine in 50 mL of tetrahydrofuran and stirred overnight at room temperature. Then the solvent was distilled off in vacuo, the residue was taken up in 30 mL of dichloromethane, this solution was washed with water, and dried with sodium sulfate. After distillation of the solvent and flash chromatography (silica gel; gradient: dichloromethane/ethanol 98.5:1.5 to 80:20), the desired compound was isolated as a brownish oil. Yield: 2.05 (72% of theory); Rf value: 0.40 (silica gel; ethyl acetate/petroleum ether=1:1).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH:6](Br)[C:5]1=[O:10])(=[O:3])[NH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]([C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:41]=1[OH:42])[CH:37]=O)([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C>C1COCC1.C(O)C>[C:1]([N:4]1[CH2:8][CH2:7][C:6](=[CH:37][C:36]2[CH:35]=[C:34]([C:30]([CH3:31])([CH3:33])[CH3:32])[C:41]([OH:42])=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=2)[C:5]1=[O:10])(=[O:3])[NH2:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: NC(=O)N1CCC(Br)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C=C2CCN(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 70 °C
Yield: 60.9 %

Procedure:
A solution of 2.0 g of N-carbamoyl-3-bromopyrrolidin-2-one (9.7 mmole) and 2.78 g of triphenylphosphine (10.6 mmole) in 30 ml of THF was stirred under heating at 70° C. for 20 hours. The reaction mixture was cooled down to room temperature, then the precipitated crystals were collected. The obtained Wittig salt (1.34 g, 2.86 mmole), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (670 mg, 2.86 mmole), and triethylamine (580 mg, 5.73 mmole) were dissolved into 60 ml of ethanol, and the mixture was stirred under heating at 70° C. for 2 hours. The reaction mixture was evaporated, then the residue was dissolved into ethyl acetate, which was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The residue was separated by using silica gel chromatography (toluene:ethyl acetate=3:1) and recrystallized from dichloromethane-n-hexane, whereby 600 mg of the objective compound was obtained in 17.1% yield. The physical constants are described on Table 1.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5]C(C1C(C)=CC=CC=1Cl)=O.[N+]([C:27]1C=C(C=CC=1)C(O)=O)([O-])=O>>[CH3:27][C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:16][C@@H:4]([C:3]([OH:2])=[O:23])[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(C)cccc1Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: Cc1cccc(C[C@H](N)C(=O)O)c1

Procedure:
N-[1-(2-Chloro-6-methylphenyl)carbonyl]-4-[[2-(3-nitrophenyl))-1-oxoethyl]amino]-3-methyl-L-phenylalanine was prepared from 4-amino-3-methyl-N-[[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (52 mg) and 3-nitrobenzoic acid (32 mg, 0.19 mmol) using the procedure described in example 120 to give 15 mg of a white powder. HR MS (C25H22N3O6Cl): Obs. Mass 496.1288. Calcd. Mass 496.1288 (M+H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:36]([O:38][CH2:39][CH2:40][CH3:41])=[O:37]>ClCCl>[CH2:33]([O:32][CH2:31][C:20]1[N:21]([CH2:22][C:23]([CH3:25])([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:24])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:36](=[O:37])[O:38][CH2:39][CH2:40][CH3:41])[C:18]=2[N:19]=1)[CH3:34]
Reactant: CCCOC(=O)Cl
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)Nc1nc2ccccc2c2c1nc(COCC)n2CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
Triethylamine (2.67 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-{2-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (1.5 g, 1 eq) in dichloromethane (150 mL). A solution of propyl chloroformate (1.55 g, 3.3 eq) in dichloromethane (5 mL) was added dropwise to give a clear solution. The reaction mixture was allowed to come to ambient temperature with stirring for 24 hours. The reaction mixture was washed sequentially with water (150 mL), 4% sodium carbonate (150 mL), water (150 mL), and brine (150 mL). The organic layer was concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-20% CMA in chloroform, 1500 mL) followed by recrystallization from diethyl ether to provide 1.23 g of propyl 2-ethoxymethyl-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white powder, mp 177-179° C. Anal calcd for C22H31N5O5S: C, 55.33; H, 6.54; N, 14.66. Found: C, 55.41; H, 6.47; N, 14.45.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C@H:14]([O:19][CH3:20])[C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@@H:14]([O:19][CH3:20])[CH2:13][N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([NH2:1])[CH:22]=[CH:21][C:7]=2[CH2:8][CH2:9]1
Reactant: CO[C@@H](CN1CCc2ccc([N+](=O)[O-])cc2CC1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](CN1CCc2ccc(N)cc2CC1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
7-Nitro-3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (171 mg, 0.538 mmol, 1.0 eq) was placed in methanol (20 mL) and 10% palladium on carbon (17 mg) was added. The reaction was hydrogenated at 25 psi for 30 minutes. The mixture was then filtered through celite and concentrated under reduced pressure to obtain 3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine as a green amorphous solid (113 mg, 73%). LCMS (m/e) 289 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.89 (d, 1H, J=7.5 Hz), 6.51-6.45 (m, 2H), 3.76-3.66 (m, 1H), 3.61 (s, 3H), 3.63-3.52 (m, 2H), 2.88-2.79 (m, 6H), 2.78-2.69 (m, 4H).