Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CCCCCCCCCCCCC=CN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent is evaporated from the combined filtrate and washings. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(OC(=O)C)(=O)C.Cl[C:24](Cl)([F:29])[C:25]([O:27][CH3:28])=[O:26]>[Zn].[Cu]Cl.O1CCCC1>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=CC1(c2ccc(OC(F)F)cc2)CC1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Yield: 28 %

Procedure:
The method of Example 1 was repeated using zinc powder (2.8 g), copper (I) chloride (0.42 g), molecular sieve 4A (2.8 g) tetrahydrofuran (50 ml), 1-(4-difluoromethoxyphenyl)-1-formylcyclopropane, acetic anhydride (1.5 ml) and methyl dichlorofluoroacetate (3.6 g) to yield the title compound (0.79 g, 28%).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[C:11](=[C:21](O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]1=[O:29])(=O)C1C=CC=CC=1.[NH2:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[C:34]#[N:35]>CN(C=O)C>[C:34]([C:33]1[CH:32]=[C:31]([NH:30]/[C:21](=[C:11]2\[C:10](=[O:29])[NH:9][C:17]3[C:12]\2=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:38]=[CH:37][CH:36]=1)#[N:35]
Reactant: O=C1C(=C(O)c2ccccc2)c2cc([N+](=O)[O-])ccc2N1C(=O)c1ccccc1
Reactant: N#Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: N#Cc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
2 g (5.2 mmol) of 1-benzoyl-3-(1-hydroxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 1.8 g (16 mmol) of 3-aminobenzonitrile are stirred in DMF for 70 hours at ambient temperature. Then the reaction solution is extracted with ether, the organic phase is washed with water and dried over sodium sulphate. After removal of the solvent in vacuo the residue is chromatographed on silica gel (dichloromethane/methanol=50:1).
Reaction SMILES: [CH:1]1(CNC(C2N(C)C=C(C(C3C(C4C=CC(F)=CC=4)=NOC=3C)=O)C=2)=O)CC1.[CH:29]1([NH:34][C:35]([C:37]2[NH:38][CH:39]=[C:40]([C:42]([C:44]3[C:45]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[CH:51]=4)=[N:46][O:47][C:48]=3[CH3:49])=[O:43])[CH:41]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([NH:34][C:35]([C:37]2[N:38]([CH3:1])[CH:39]=[C:40]([C:42]([C:44]3[C:45]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[CH:51]=4)=[N:46][O:47][C:48]=3[CH3:49])=[O:43])[CH:41]=2)=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCCC2)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1cc(C(=O)NCC2CC2)n(C)c1
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)c1cc(C(=O)NC2CCCC2)n(C)c1
Yield: 27.6 %

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4fluorophenyl)-isoxazole-4-carbonyl)-1-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid cyclopentylamide (example 178) in 27.6% yield as white solid. (m/e): 396.2 (M+1; 100%).
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([C:6](=O)[C:7]([OH:9])=[O:8])=[N:2]1.[C:11]([O:15][C:16]([CH2:18][O:19][NH2:20])=[O:17])([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>O1CCCC1.O>[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:6]([C:3]1[CH:4]=[N:5][S:1][N:2]=1)[C:7]([OH:9])=[O:8])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)C(=O)c1cnsn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1cnsn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of (1,2,5-thiadiazol-3-yl)glyoxylic acid (6 g) in tetrahydrofuran (30 ml) and water (30 ml) was added tert-butoxycarbonylmethoxyamine (8.37 g) at room temperature. The mixture was adjusted to pH 4.5-5.0 with 4 N aqueous sodium hydroxide and stirred at ambient temperature for 4 hours. The mixture was adjusted to pH 7.5 with 4 N aqueous sodium hydroxide and washed with ethyl acetate (100 ml×2). The aqueous layer was acidified to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (100 ml×2). The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated in vacuo to give 2-(tert-butoxycarbonylmethoxyimino)-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn and anti mixture) (10.02 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)CCC>O>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:2]1[CH:7]=[CH:6][C:5]([C:16]2[O:15][CH:14]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Brc1ccc(Br)cc1
Solvent: O
Product: c1coc(-c2ccc(-c3ccco3)cc2)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
To a stirred solution of 1,4-dibromobenzene (5 mmol) was added palladium tetrakis-triphenylphosphine (400 mg). The reaction mixture was kept stirring for 15 min after which 2-tributylstannylfuran (10 mmol) was added and the reaction mixture was refluxed at 100° C. for 24 h. The solvent was then evaporated to dryness to give a dark brown residue that was suspended in water and extracted with CH2Cl2. The organic layer was passed over hyflo, dried (Na2SO4) and evaporated to dryness under reduced pressure to give 15 in 91% yield; mp 149-150° C. 1H NMR (DMSO-d6); δ 6.62 (d, 2H), 7.01 (d, 2H), 7.76-7.79 (m, 6H). MS (ESI) m/e (rel. int.): 210 (M+, 100), 181 (40), 153 (30). Anal. Calc. for C14H10O2: C %, 79.98; H %, 4.79; Found. C %, 80.12; H %, 4.59.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][C:29](=O)[CH3:30])[CH2:10]1)(=[O:8])=[O:7].[O:32]1[CH2:35][CH:34]([NH2:36])[CH2:33]1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[F:25][C:22]([F:23])([F:24])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:7])=[O:8])[CH2:10][C@@H:11]2[CH2:28][CH:29]([NH:36][CH:34]2[CH2:35][O:32][CH2:33]2)[CH3:30])=[CH:20][CH:19]=1)([OH:27])[CH3:26]
Reactant: CC(=O)C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: NC1COC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)NC1COC1
Reaction time: 3 h
Yield: 25 %

Procedure:
A solution of 1-((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)-2-propanone (100 mg, 0.210 mmol) and oxetan-3-amine (18.41 mg, 0.252 mmol, J & W PharmLab, Levittown, Pa.) in THF (10 mL) was cooled to 0° C. To this mixture was added Ti(O-iPr)4 (154 μL, 0.525 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was stirred for 3 h and then a solution of sodium borohydride (11.91 mg, 0.315 mmol, Sigma-Aldrich, St. Louis, Mo.) in MeOH (1 mL) was added. The reaction mixture was stirred at ambient temperature for 4 h. Saturated aqueous NH4Cl was added and the mixture was filtered. The filtrate was concentrated and purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in MeCN/H2O (5% to 100% over 15 min) to give 1,1,1-trifluoro-2-(4-((2S)-2-(2-(3-oxetanylamino)propyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (28 mg) as a mixture of four isomers
Reaction SMILES: C(Cl)(Cl)=O.COC1C=C(C(F)(F)F)C=C(C=1)N.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:23]=[C:24]([N:26]=[C:27]=[O:28])[CH:25]=1.[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48]3[CH:53]=[C:52]([NH:54][CH3:55])[N:51]=[CH:50][N:49]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)[CH3:34].C([O-])(O)=O.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:23]=[C:24]([NH:26][C:27](=[O:28])[N:54]([C:52]2[CH:53]=[C:48]([NH:47][C:44]3[CH:43]=[CH:42][C:41]([N:38]4[CH2:37][CH2:36][N:35]([CH2:33][CH3:34])[CH2:40][CH2:39]4)=[CH:46][CH:45]=3)[N:49]=[CH:50][N:51]=2)[CH3:55])[CH:25]=1
Reactant: COc1cc(N=C=O)cc(C(F)(F)F)c1
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Agent: COc1cc(N)cc(C(F)(F)F)c1
Agent: O=C(Cl)Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4cc(OC)cc(C(F)(F)F)c4)ncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Phosgene (20% in toluene, 1.62 mL, 3.0 mmol, 2.0 equiv) is added to a solution of 5-methoxy-3-trifluoromethylaniline (344 mg, 1.8 mmol, 1.2 equiv) in dioxane (6 mL) under a nitrogen atmosphere. The mixture is heated to reflux, stirred for 80 min, allowed to cool to RT, and concentrated in vacuo. During 45 min, a concentrated solution of the resulting oily 5-methoxy-3-trifluoromethyl-phenylisocyanate in toluene is added portion-wise to a boiling solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (468 mg, 1.50 mmol; Step 242.1) in 18 ml of toluene under a nitrogen atmosphere. The reaction mixture is stirred at 110° C. for 4 h, allowed to cool to RT, and diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with brine, dried (Na2SO4), filtered and concentrated. Column chromatography (DCM/MeOH, 49:1→24:1) provides the title compound: API-MS: 530/532 [MH]+; TLC: Rf=0.4 (DCM/MeOH, 9:1); tR=4.3 min (purity: 100%, system 1).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]1[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])=[CH:14][C:15]([CH3:16])=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: NNCc1ccccc1
Agent: Cl
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(Cc2ccccc2)n1

Procedure:
Prepare the compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and benzylhydrazine hydrochloride according to the procedure of Example 28.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13]I)[CH2:6][CH2:5]2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:6][CH2:5]2
Reactant: C1COCCN1
Reactant: CS(=O)(=O)Nc1cccc2c(C3(CCCI)CCc4cc(F)ccc43)c[nH]c12
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc2c(C3(CCCN4CCOCC4)CCc4cc(F)ccc43)c[nH]c12
Yield: 83 %

Procedure:
Combine N-{3-[5-fluoro-1-(3-iodo-propyl)-indan-1-yl]-1H-indol-7-yl}-methane sulfonamide (65 mg, 0.13 mmol) and morpholine (2 ml) in anhydrous tetrahydrofuran (2.5 ml) and stir at room temperature under nitrogen overnight. Remove the volatiles under high vacuum, dissolve the residue in dichloromethane, add solid potassium carbonate, stir for ten minutes, filter, and concentrate in vacuo. Purify the residue on silica eluting with 5 to 10% methanol in dichloromethane over 15 minutes to obtain the title compound as a white solid (50 mg, 83%). LC-MS m/z 472.2 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:45][CH:46]([CH3:48])[CH3:47]>CN(C=O)C.O>[CH2:45]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]1=[O:19])[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)CBr
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC(C)C)c3ncccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.9 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (100 mg, 0.21 mmol) in DMF (5 ml) were added potassium carbonate (1.39 g, 10.1 mmol), potassium iodide (10 mg, 0.07 mmol) and 1-bromo-2-methylpropane (58 mg, 0.43 mmol), and the mixture was stirred at room temperature for five hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1-3% methanol in chloroform) to give the title compound (71 mg, 0.13 mmol).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[CH2:2][CH2:3][CH3:4].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][O:25][CH2:26][C:27]([NH2:29])=[NH:28])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:29][C:27](=[NH:28])[CH2:26][O:25][CH2:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(Cl)c(C(=O)O)c1
Reactant: N=C(N)COCCc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cccc(Cl)c2)c1

Procedure:
In analogy to the procedure described in example 78.3, 5-butyl-2-chloro-nicotinic acid was reacted with 2-[2-(3-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 79.2) in the presence of TBTU and DIPEA to give 5-butyl-2-chloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as yellow oil. MS: m/e=408.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:15][C:16]1[N:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][CH:26]=1>>[NH2:15][C:16]1[C:17]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH2:32])=[O:33])=[CH:27][CH:26]=2)=[CH:18][C:19]([C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH:12]3[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[CH:20][N:21]=1
Reactant: NC(=O)c1ccc(-c2cc(B(O)O)cnc2N)cc1
Reactant: O=S(=O)(NC1CC1)c1ccc(Br)cc1
Product: NC(=O)c1ccc(-c2cc(-c3ccc(S(=O)(=O)NC4CC4)cc3)cnc2N)cc1
Yield: 47.3 %

Procedure:
General method B was applied to 4-bromo-N-cyclopropylbenzenesulfonamide (41 mg, 0.15 mmol), 6-amino-5-(4-carbamoylphenyl)pyridin-3-ylboronic acid (53 mg, 0.15 mmol), to give 4-(2-amino-5-(4-(N-cyclopropylsulfamoyl)phenyl)pyridin-3-yl)benzamide as a white solid (29 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, J=2.3 Hz, 1H), 8.03 (br. s., 1H), 7.98 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 7.87 (d, J=2.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.76 (d, J=1.5 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.37 (br. s., 1H), 6.06 (br. s., 2H), 2.06-2.13 (m, 1H), 0.42-0.50 (m, 2H), 0.35-0.42 (m, 2H); MS (EI) m/z: 409 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[O:23][NH:22][C:21](=O)[CH:20]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:20]=1)=[O:18]
Reactant: COC(=O)c1cc(=O)[nH]o1
Reactant: Cc1onc(-c2ccccn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (465 mg, 2.44 mmol) in THF (10 mL) was added 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (350 mg, 2.45 mmol) and triphenylphosphine (769 mg, 2.93 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.23 mL, 2.68 mmol) was added and the reaction mixture was stirred for 1 h at 0° C. and then overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4) afforded the title compound (443 mg, 57%) as a white solid. MS: m/e=316.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C(C)=CC=CC=1C>[Pd].O1CCCC1>[CH2:1]([C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[O:16])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(C(=O)Cl)cc1
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc(C=O)cc1
Yield: 77.1 %

Procedure:
Rosenmund Reduction--Hydrogenate a mixture of 4-(n-decyl)benzoyl chloride (28 g., 0.1 mol), 10% palladium on carbon (2 g.), 2,6-lutidine (10.9 g., dried over KOH and distilled), and tetrahydrofuran (THF) (300 ml., distilled from LiAlH4) in a Paar apparatus for 30 min. at 25° C. under an H2 atmosphere (62 psi). Filter the resulting mixture and collect the catalyst. Wash the catalyst with THF. Evaporate the filtrate and partition the residue between diethyl ether and H2O. Wash the combined organic solutions with aqueous HCl (0.1N) and NaHCO3 (0.1N) solutions. Evaporate the solvent from the dried organic solution to give a liquid. Distill the liquid to give 4-(n-decyl)benzaldehyde (19 g. 77% yield, b.p. 152°-156° C. at 0.3 mm).
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[F:7][C:8]([F:30])([F:29])[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[O:28])[N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:15]2[CH2:18][C:19](OCC)=[O:20])=[CH:11][CH:10]=1>C(O)C.C(OCC)C>[CH2:24]([N:14]1[C:13](=[O:28])[C:12]2[C:16](=[CH:17][C:9]([C:8]([F:7])([F:29])[F:30])=[CH:10][CH:11]=2)[CH:15]1[CH2:18][C:19]([NH:5][C:4]([NH2:6])=[NH:3])=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)CN1C(=O)c2ccc(C(F)(F)F)cc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h
Yield: 7.6 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 10 cm3 of absolute ethanol, 0.13 g of sodium, 0.52 g of guanidinium chloride and 1.25 g of ethyl (6-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in a mixture of 5 cm3 of water and 15 cm3 of diethyl ether and then concentrated to dryness again under the same conditions. The residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with twice 50 cm3 of aqueous 1N sodium hydroxide solution and then with 30 cm3 of aqueous 4N hydrochloric acid solution. The acidic aqueous phase is treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 50 cm3 of ethyl acetate. The organic extracts are combined and washed with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The white solid thus obtained is taken up in 20 cm3 of diethyl ether and stirred at a temperature in the region of 20° C., and then filtered. The solid is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 0.099 g of N-[2-(2-Isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a pale yellow solid melting at 154° C. Mass spectrum: EI: m/e 356 (M+), m/e 269, m/e 200, m/e 86 (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[CH3:18][S:19]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:16])([F:15])[F:17])=[CH:12][C:2]=1[Cl:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOc1ccc(OC(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOc1ccc(OC(F)(F)F)cc1Cl
Yield: 98.4 %

Procedure:
To a solution of 3-(2-chloro-4-trifluoromethoxyphenoxy)-propanol (20 g, 0.074 mole) in 100 mL of dichloromethane at 0° C. was added methanesulfonyl chloride (6.83 mL, 0.089 mole) and triethylamine (20.5 mL, 0.148 mole). The resulting solution was stored in a refrigerator overnight. The solution was then washed with 100 mL of cooled, diluted HCl-H2O solution. The organic layer was separated, dried over MgSO4, filtered and evaporated of solvent to yield 25.4 g of the product.
Reaction SMILES: C(N(CC)CC)C.C(O[C@@H:12]1[C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH2:16][CH3:17])[C:14](=[O:33])[CH2:13]1)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH:21]([Cl:32])[CH2:20]3)(=O)C.O>C(O)C>[Cl:32][CH:21]1[C:22]2[C@H:27]([CH2:26][CH2:25][C:24](=[O:31])[CH:23]=2)[C@@H:28]2[C@H:19]([C@H:18]3[C@@:15]([CH2:30][CH2:29]2)([CH2:16][CH3:17])[C:14](=[O:33])[CH:13]=[CH:12]3)[CH2:20]1
Reactant: CC[C@]12CC[C@H]3[C@@H](CC(Cl)C4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@]12CC[C@H]3[C@@H](CC(Cl)C4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
Triethylamine (0.5 ml, 3.6 mmol) was added to a suspension of 15α-acetoxy-6-chloro-18-methyl-estra-4-en-3,17-dione (0.5 g, 1.32 mmol) in ethanol (15 ml). The mixture was stirred at 45° C. for 2 h, cooled to 10° C. and water (4 ml) was then added. The precipitate was filtered and washed with an ethanol/water (1/1) mixture. The crude product was crystallized from ethanol and dried under vacuum to afford 6-chloro-18-methyl-estra-4,15-dien-3,17-dione (0.26 g, yield: 62%).