Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][Br:19])[CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CCOC(=O)c1cccc(-c2ccccc2C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(-c2ccccc2CBr)c1

Procedure:
2′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 2′-Methyl-biphenyl-3-carboxylic acid ethyl ester (8.3 g, 34.54 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (7.38 g, 41.45 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.28 g, 1.73 mmol, 5 mol %). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1.Br[CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1
Reactant: CCCBr
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Product: CCCOc1ccc(CN2C(=O)CCCC2c2c(OC)cccc2OC)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one with commercially available 1-bromopropane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.79 min.; [M+H]+: 384.19 g/mol.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[CH2:6]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]([OH:25])[C:20](=[NH:24])[O:21]CC)[CH3:7].O1CCCC1>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]1[O:25][C:1](=[O:2])[NH:21][C:20]1=[O:24])[CH3:7]
Reactant: CCOC(=N)C(O)c1c(OCC)ccc2ccccc12
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc2ccccc2c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 3, using a reaction time of 64 hours at room temperature following the cold phosgene perfusion, ethyl 1-(2-ethoxy-1-naphthyl)-1-hydroxymethanecarboximidate hydrochloride (5.0 g., 16.1 mmoles) in 200 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-ethoxy-1-naphthyl)oxazolidine-2,4-dione (0.57 g., m.p. 221°-224° C., m/e 271).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1/[CH:13]=[N:15]/[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1nccn1Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3nccn3Cc3ccccc3)cccc21
Yield: 100.1 %

Procedure:
The mixture of 1-benzyl-1H-imidazole-2-carbaldehyde (430 mg, 1.48 mmol), 4-aminoisobenzofuran-1(3H)-one (221 mg, 1.48 mmol) and magnesium sulfate (4.3 g) in acetonitrile was heated to reflux for 48 hr. Then the mixture was filtrated off and evaporated to remove the solvent. The crude was re-crystallized from isopropanol to obtain the title compound (470 mg, 65%). LC-MS (ESI) m/z: 318 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]2.FC(F)(F)C(O)=O.[N+:24]([O-])([O-:26])=[O:25].[Na+].C(=O)(O)[O-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:24]([O-:26])=[O:25])=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]2
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cccc2c1CC(NC(C)=O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([N+](=O)[O-])c2c1CC(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 219 mg. (1 mmol) of N-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl) acetamide in 7.5 ml. of trifluoroacetic acid was treated with 140 mg. of sodium nitrate in one portion. It was stirred for one hour at room temperature, poured into excess sodium bicarbonate solution and extracted well with methylene chloride. The combined extracts were washed with water, dried and evaporated to give crystals. Recrystallization from ethyl acetate gave N-(1,2,3,4-tetrahydro-8-methoxy-5-nitro-2-naphthalenyl) acetamide as white crystals m.p. 205°-206°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[C:24](O)(=[O:27])[CH2:25][CH3:26]>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:24](=[O:27])[CH2:25][CH3:26])[CH:11]=[N:10][CH:9]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)ccc21
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)NCCOc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1

Procedure:
In analogy to the procedure described for the preparation of example 37, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 42) has been reacted with propionic acid to give the title compound as a white solid. MS: 354.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH:7][C:13](=[O:14])[C:12]([F:19])([F:18])[F:11]
Reactant: NCCc1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Product: O=C(NCCc1cccc(Br)c1)C(F)(F)F

Procedure:
Condensation of 3-bromophenethylamine with ethyl trifluoroacetate gave N-(3-bromophenethyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (3.30 g, quant.). 1H NMR (400 MHz, CDCl3) δ 7.40 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 7.53 (t, J=1.8 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.10-7.13 (m, 1H), 6.32 (br s, 1H), 3.61 (q, J=6.7 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[B:17]([OH:18])[OH:16]
Reactant: COB(OC)OC
Reactant: COc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 105.3 %

Procedure:
n-Butyllithium (1.6M in hexane, 13.0 mL) was added to a stirred, cooled (-78° C.) solution of 2-bromoanisole (3.74 g) in tetrahydrofuran (20 mL) and the mixture was stirred at -78° C. for 20 min. Trimethylborate (5.92 g) was added and the solution was allowed to warm to room temperature and stirred for 24 h. The mixture was cooled to 0° C. and acidified with aqueous hydrochloric acid (5M). The mixture was extracted with dichloromethane (4×50 mL) and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (3.2 g), δH (CDCl3) 3.91 (3H, s), 6.09 (2H, s), and 6.87-7.03 (4H, m).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[F:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:9]=[CH:10][CH:11]=1>CN(C=O)C>[F:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:3])[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CI
Reactant: O=C(Nc1cccc(F)c1)c1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cccc(I)c1)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
Sodium hydride (1.11 g of 60% NaH in mineral oil) was added to a solution of CH3I (4.53 g) and N-(3-fluorophenyl)-3-iodobenzamide (7.26 g) in DMF (120 mL) at 0° C. under nitrogen. After being stirred at 0° C. for another 5 minutes, the reaction was stirred at room temperature under nitrogen for 4 h. The reaction was quenched by slow addition of saturated aqueous NH4Cl (120 mL), followed by addition of water (100 mL). The mixture was extracted with diethyl ether (300 mL×2). The combined ether layers were washed by water (150 mL×4) and brine (150 mL×1), dried by Na2SO4 and concentrated to give crude product (7.56 g), which was purified by column chromatography to afford N-(3-fluoro-phenyl)-3-iodo-N-methylbenzamide (5.88 g; 78%). 1H NMR (600 MHz, DMSO-d6) δ 7.64 (m, 2H), 7.28 (m, 1H), 7.24 (d, 1H, J=7.5 Hz), 7.19 (m, 1H), 7.04-6.99 (m, 3.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]O.P(Br)(Br)[Br:15]>C(OCC)C>[Br:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: Cn1nc(C(F)(F)F)c(CO)c1Cl
Solvent: CCOCC
Product: Cn1nc(C(F)(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of 8.3 g (38.7 mmoles) of (5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 12.6 g (46.4 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 10.7 g (yield: 99.9%) of 4-bromomethyl-5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+].[C:9]([C:11]1[CH:12]=[C:13]([N:18]([C:22]2[NH:23][C:24](=[O:32])[NH:25][C:26](=[O:31])[C:27]=2[CH:28]([CH3:30])[CH3:29])[C:19](=[O:21])[CH3:20])[CH:14]=[C:15]([CH3:17])[CH:16]=1)#[N:10].Br[CH2:34][C:35]1[CH:40]=[C:39]([F:41])[N:38]=[C:37]([NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[CH:36]=1>CN(C)C=O>[C:9]([C:11]1[CH:12]=[C:13]([N:18]([C:22]2[N:23]([CH2:34][C:35]3[CH:36]=[C:37]([NH:42][CH2:43][C:44]4[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=4)[N:38]=[C:39]([F:41])[CH:40]=3)[C:24](=[O:32])[NH:25][C:26](=[O:31])[C:27]=2[CH:28]([CH3:30])[CH3:29])[C:19](=[O:21])[CH3:20])[CH:14]=[C:15]([CH3:17])[CH:16]=1)#[N:10]
Reactant: CC(=O)N(c1cc(C)cc(C#N)c1)c1[nH]c(=O)[nH]c(=O)c1C(C)C
Reactant: COc1ccc(CNc2cc(CBr)cc(F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cn3c(N(C(C)=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Yield: 55.6 %

Procedure:
Potassium carbonate (25 mg, 0.18 mmol) and lithium chloride (24 mg, 0.18 mmol) were added to a solution of N-(3-cyano-5-methyl-phenyl)-N-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-acetamide (60 mg, 0.18 mmol) and (4-bromomethyl-6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (59 mg, 0.18 mmol) in dimethylformamide (1 mL). After 17 hours the solvent was removed and the residue was subjected to flash chromatography (eluant: 0-5% methanol/dichloromethane). The product containing fractions were combined and the solvent was removed in vacuo to yield the product (58 mg, 0.10 mmol). C31H31FN6O4 calculated 570.2, observed [M+1]+ 571.1; rt=3.82 min.
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([OH:9])(=O)[CH3:7].[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C#C.C#C.[Zn]>[CH:12]([C@@H:11]1[O:10][C@H:7]1[CH2:6][OH:9])=[C:13]=[CH:14][C:11]#[C:12][C:13]#[CH:14]
Reactant: C1CCOC1
Reactant: CC(=O)O
Agent: C#C
Agent: CS(=O)(=O)Cl
Agent: [Zn]
Product: C#CC#CC=C=C[C@@H]1O[C@H]1CO
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a separate flask, the mesylate of 6-[(tetrahydro-2H-pyran-2-yl)oxy]-4-hexen-1-yn-3-ol was prepared via the following procedure. To a stirred solution of 6-(tetrahydro-2H-pyran-2-yl)oxy]-4-hexen-1-yn-3-ol (98 mg, 0.5 mmole), anhydrous lithium bromide (43 mg, 0.5 mmole) and a few milligrams of 1,10-phenanthroline in 5 ml of tetrahydrofuran at -78° C. was added n-butyllithium dropwise until a brown color was obtained (ca. 0.5 mmole of n-butyllithium). The mixture was stirred for one-half hour whereupon mesyl chloride (38 μl, 0.5 mmole) was added dropwise. The brown color discharged to yellow. The solution was stirred for 10 minutes at -78° C. and was then added all at once (via short teflon cannula and argon pressure) to the above stirred -20° C. solution of zinc diacetylene. The resultant mixture was stirred at -20° C. for 15 minutes and was then acidified by the addition of a solution of acetic acid in tetrahydrofuran. The mixture was then concentrated to ca. 1/4 volume and 30 ml of a mixture of ether-hexane 1:1 was added with stirring whereupon a gum separated. The supernatant was then filtered through a pad of silica gel. The filtrate was concentrated to dryness and immediately redissolved in a few ml of ether-hexane 1:5 (some solid did not dissolve). This solution of crude product was then purified via flash chromatography (LPS-1 silica gel, ether-hexane 1:10) to afford pure title compound (30 mg). This allene was stored in solution in ether-hexane in the freezer.
Reaction SMILES: C([O:9][C@H:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][C@@H:11]1[C:18]1[N:22]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]=[CH:20][CH:19]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:17][C:13]1([F:16])[CH2:14][CH2:15][C@H:10]([OH:9])[C@@H:11]([C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]=[CH:20][CH:19]=2)[CH2:12]1
Reactant: COCCOCn1nccc1[C@H]1CC(F)(F)CC[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOCn1nccc1[C@H]1CC(F)(F)CC[C@@H]1O
Yield: 100.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107e by using the (1S*,2R*)-4,4-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl benzoate (547 mg, 1.39 mmol) prepared in Example 157b, potassium carbonate (19 mg, 0.139 mmol) and methanol (10 mL), to yield the title compound (404 mg, 99%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([O:12][CH3:13])[C:7]([NH2:11])=[N:8][C:9]=1[CH3:10].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23].ClCCl.C(O)(=O)C>CN1CCCC1=O>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:11][C:7]1[C:6]([O:12][CH3:13])=[N:5][C:4]([Br:3])=[C:9]([CH3:10])[N:8]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1nc(Br)c(C)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: COc1nc(Br)c(C)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
Sodium hydride (0.5 g of a 60% dispersion in oil) was added to a solution of 5-bromo-3-methoxy-6-methyl-2-pyrazinamine (Example 118c) (0.55 g) in N-methylpyrrolidinone (25 mL). The resultant dark solution was stirred at room temperature for 0.5 h before a solution of 2,3-dichlorobenzenesulphonyl chloride (0.67 g) in N-methylpyrrolidinone (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 h, then quenched with aqueous ammonium chloride and partitioned between ethyl acetate and aqueous ammonium chloride (×5). the organic phase was dried (MgSO4), filtered and evaporated to give the crude product. Chromatography on silica gel eluting with dichloromethane/acetic acid (200:1) gave the title compound as a pale yellow solid (0.38 g).
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[C:16]1([CH2:22][O:23][C:24](=[O:33])[NH:25][CH2:26][C@H:27]2[C@@H:31]([OH:32])[CH2:30][NH:29][CH2:28]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[C:16]1([CH2:22][O:23][C:24](=[O:33])[NH:25][CH2:26][C@H:27]2[C@@H:31]([OH:32])[CH2:30][N:29]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][C:4]=3[F:15])[CH2:28]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2n1
Yield: 96 %

Procedure:
To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (0.73 g, 3.60 mmole) in EtOH (5 mL) was added (±)-phenylmethyl{[cis-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (0.90 g, 3.60 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (1.57 g, 96%) as a light yellow foam: LC-MS (ES) m/e 455 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C@@:18]2([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19]2)=[O:16])[CH:12]=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[C:43]([F:46])([F:45])[F:44])=[CH:30][CH:29]=1>>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([NH:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:23]([C@:18]3([NH:17][C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=[N:13][CH:12]=4)=[O:16])[CH2:22][CH2:21][O:20][CH2:19]3)=[O:24])=[N:33][CH:32]=2)=[C:36]([C:43]([F:46])([F:44])[F:45])[CH:37]=1
Reactant: COc1ccc(Nc2ccc(CN)nc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cncc(NC(=O)OC(C)(C)C)c4)CCOC3)nc2)c(C(F)(F)F)c1

Procedure:
Analogously to Example 1e), (S)-3-[(5-tert-butoxycarbonylamino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (product from Example 5d, 1.7 mmol) was reacted with (6-aminomethyl-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine (product from Example 5b, 1.7 mmol). The product was purified by chromatography (silica gel, dichloromethane with 0-10% methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13]C(=O)C2C=CC([N+]([O-])=O)=C(C)C=2)=[CH:9][CH:8]=1)=[O:6].C(O)C.[OH-].[Na+]>O>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([C:4]2[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:2]([CH3:1])[CH:3]=2)=[O:6])=[CH:8][CH:9]=1
Reactant: Cc1cc(C(=O)Oc2ccc(C(=O)c3ccc([N+](=O)[O-])c(C)c3)cc2)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)c2ccc(O)cc2)ccc1[N+](=O)[O-]

Procedure:
322 g (1 mol) of 4-nitro-4′-(4-nitrobenzoyloxy)benzophenone (example 4.1) are heated in 1.3 l of water, 200 ml of ethanol and 85 g of sodium hydroxide until the solid has dissolved.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>[H-].[Na+].CN(C)C=O>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1
Reactant: Clc1cccc(OCc2ccccc2)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2cccc(OCc3ccccc3)n2)c1
Yield: 78.8 %

Procedure:
The procedure of Example 4a) was also used to introduce the 3-trifluoromethyl phenoxy group by reaction of 2-benzyloxy-6-chloropyridine (5 g; 23 mmols) from a) above with 3-trifluoromethylphenol (3.3 g; 0.018 mols) using dry sodium hydride (0.55 g) and dry dimethylformamide (200 ml) as solvent, with a 1 hour reflux stage. 2-(3-Trifluoromethylphenoxy)-6-benzyloxypyridine (4.9 g; 51%) was obtained as a yellow oil following solvent extraction (chloroform/water--500 ml; 50/50), and chromatography plus distillation of the organic layer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:17])([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21](OCC)(OCC)OCC)[CH3:19]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([F:17])[C:9]([CH3:11])([CH3:10])[O:12][C:21]([O:20][CH2:18][CH3:19])=[N:16][S:13]2(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(F)(c1cccc(Br)c1)S(N)(=O)=O
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)O
Product: CCOC1=NS(=O)(=O)C(F)(c2cccc(Br)c2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 75 mg of 1-(3-bromophenyl)-1-fluoro-2-hydroxy-2-methylpropane-1-sulfonamide in 5 ml of tetraethoxymethane and 1 ml of acetic acid was stirred at 100° C. for 1.5 hours. The conversion was checked by LCMS. Since it was incomplete, the reaction mixture was stirred at 100° C. for a further 3.5 hours. After the removal of the solvents under reduced pressure, the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (45.6 mg) with a molecular weight of 380.2 g/mol (C13H15BrFNO4S).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([I:11])=[N:6]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: BrC1CCCC1
Product: Fc1ccc2c(c1)c(I)nn2C1CCCC1
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield from 5-fluoro-3-iodo-indazole and bromocyclopentane according to the procedure for Preparation 11A. The minor isomer was not isolated cleanly. 1H NMR (400 MHz, CDCl3): δ 1.69-1.76 (2H, m), 1.92-1.98 (2H, m), 2.12-2.18 (4H, m), 4.87-4.95 (1H, m), 7.08 (1H, dd, J=8.2, 2.3 Hz), 7.17 (1H, td, J=8.9, 2.4 Hz), 7.35 (1H, dd, J=9.1, 4.0 Hz). [M+H] calc'd for C12H12FIN2, 331; found 331.
Reaction SMILES: NN.Br.[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=2)[S:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C>[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=2)[S:14][CH2:15][CH2:16][NH2:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1CCSc1cccc(CN2CCCCC2)c1
Agent: Br
Agent: NN
Solvent: CCO
Product: NCCSc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
Anhydrous hydrazine (1.79 g, 56.0 mmoles) was added to a suspension of N-{2-[3-(piperidinomethyl)thiophenoxy]ethyl}phthalimide hydrobromide (5.17 g, 11.2 mmoles) [prepared in Step D] in 200 mL of 95% ethanol, stirred at ambient temperature for 18 hours and filtered. The filtrate was stripped and the semi-solid residue was stirred with several portions of ether. Evaporation of the solvent gave 2.8 g of title compound as a yellow oil.