Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O.C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cc1O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1O
Yield: 76.9 %

Procedure:
Piperidine (0.25 mL, 2.5 mmol) was added to a suspension of 3-hydroxy-4-methoxybenzaldehyde (0.39 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.50 g, 2.2 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3-Hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.53 g, 76%) was obtained as a yellow crystalline solid; mp 215-216° C., lit [25] 219-222° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 6.59 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6′=8.5 Hz, 1H, H5′), 7.10-7.13 (m, 2H, H2′, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.47 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.99 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[C:11](=[O:17])[N:10]([CH3:18])[CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:7][C:6]=1[C:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[C:11](=[O:17])[N:10]([CH3:18])[CH:9]=1
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)n2cncc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)n2cncc2c1=O
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of the title compound from Example 129, Step 2 (140 mg, 0.38 mmol) in THF (20 ml) was added pyridine (152 mg, 1.90 mmol). Then methanesulfonyl chloride (48 mg, 0.46 mmol) was added to the solution at 0° C. The solution was allowed to warm up to room temperature and heated to reflux for overnight. The reaction mixture was concentrated under reduced pressure to yield the crude product that was purified by prep-HPLC to give the title compound (75.26 mg, 44%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.15 (s, 1H), 7.50 (d, J=2.8 Hz, 1H), 7.30 (dd, J=8.8, 2.4 Hz, 1H), 7.18 (td, J=8.8, 5.3 Hz, 1H), 7.00-6.88 (m, 2H), 6.83 (s, 1H), 6.78 (d, J=8.8 Hz, 1), 3.60 (s, 3H), 3.03 (s, 3H). LCMS: 447.0 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.Cl[C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3.5 h

Procedure:
4-methyl-1H-imidazole (1) (36.53 mmol, 1 eq) of was dissolved in 120 mL of dimethylformamide, triethylamine (73.06 mmol, 2 eq.) and chlorotriphenylmethane (40.1 mmol, 1.1 eq) where added. The mixture was stirred for 3.5 h. The precipitate filtered off and was washed by means of ice-cooled dimethylformamide (2×50 mL) and water (2×50 mL). After removal of the solvent the remaining product was dried over P4O10.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:3]=1[C:23]([NH2:25])=[O:24].C([O-])=O.[NH4+]>[Pd].CO>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: Cc1ccc(-c2nn(-c3cccc([N+](=O)[O-])c3)c(N)c2C(N)=O)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(-c2nn(-c3cccc(N)c3)c(N)c2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.7 %

Procedure:
10% Palladium on carbon (100 mg) was added to a de-gassed solution of the compound of Example 20 (120 mg, 0.36 mmol) and ammonium formate (30 mg, 4.8 mmol) in methanol. The reaction was stirred at room temperature and under nitrogen for 18 h. The reaction mixture was filtered through a pad of Celite® and ethanol removed under reduced pressure. The residue was purified by column chromatography (SiO2, ethyl acetate) to give the title compound (13 mg) as yellow crystals after trituration with diethyl ether m.p. 220-222°. δH (CDCl3) 7.45 (2H, d, J 8.0 Hz), 7.30-7.20 (3H, m), 6.90 (1H, d, J 7.9 Hz), 6.81 (1H, s), 6.62 (1H, d, J 8.0 Hz), 5.41 (2H, br s), 2.63 (2H br s) and 2.39 (3H, s). MS (ES+) 308 (MH+, 100%).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][CH3:18])[CH2:22][CH2:23]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CCN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 4-N-propylpiperidine (18 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. LC/MS showed the presence of the target compound and no starting material after 24 h. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a white solid. This solid was triturated in acetone, filtered, washed with acetone and diethyl ether to give the title compound (15 mg, 38%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4cccc(OC(F)(F)F)c4)noc3N)CC2)c1
Yield: 66.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (562 mg, 1.22 mmol, 66%) was obtained.
Reaction SMILES: [CH2:1]([O:19][P:20]([CH2:41][C:42]1[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([OH:52])=[C:44](C(C)(C)C)[CH:43]=1)(=[O:40])[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[ClH:57]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:19][P:20]([CH2:41][C:42]1[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([OH:52])=[C:44]([Cl:57])[CH:43]=1)(=[O:40])[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCCCCCCCCCCCCCCCCCC
Reactant: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1cc(Cl)c(O)c(C(C)(C)C)c1)OCCCCCCCCCCCCCCCCCC
Reaction time: 3 h

Procedure:
80.5 g of 3,5-di-tert. butyl-4-hydroxybenzyl-phosphonic acid di-n-octadecyl ester are dissolved in 250 ml of carbon tetrachloride and the solution is treated briefly with hydrogen chloride gas. The chlorination is effected by carefully bubbling in 10.5 g of chlorine gas for 3 hours at -5° C. The reaction mixture is allowed to come to room temperature and after stirring for a further 3 hours the solvent is removed in vacuo. The oily residue is digested with acetonitrile to purify the reaction product and the cyrstalline precipitate is isolated. The product is further purified by recrystallisation from aqueous ethylene glycol monomethyl ether. The resultant 3-chloro-5-tert. butyl-4-hydroxybenzyl-phosphonic acid di-n-octadecyl ester (stabiliser 3) forms white crystals with a melting point of 55° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C1([Li])C=CC=CC=1.[CH3:17][N:18]=[C:19]=[S:20].Cl>C1C=CC=CC=1.CCOCC.O.C1C=CC=CC=1>[CH3:1][O:2][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:19]([NH:18][CH3:17])=[S:20]
Reactant: COCc1ccccn1
Reactant: CN=C=S
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CNC(=S)C(OC)c1ccccn1
Reaction time: 0.5 h

Procedure:
2-(Methoxymethyl)pyridine (4.4 g., 0.036 mole), dissolved in 25 ml. of dry benzene, is added dropwise to 20 ml. of 2M phenyl lithium (0.04 mole) in benzene/ether with cooling. The mixture is stirred for 30 minutes, then methyl isothiocyanate (2.6 g., 0.03 mole), dissolved in 40 ml. of dry benzene, is added dropwise with cooling. The resulting solution is stirred overnight. An equal volume of water is added and the solution is cooled and made acidic with 10% hydrochloric acid. The phases are separated, the organic phase is washed with water and the combined aqueous phases are made basic to about pH 9 then extracted with chloroform. The chloroform extracts are washed with water and dried over magnesium sulfate. Filtration and removal of solvent gives a residue which is recrystallized from isopropyl ether/ethanol to give 2-methoxy-N-methyl-2-(2-pyridyl)thioacetamide, m.p. 104°-105°C.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7].Br>O>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:26])[C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)Oc1ccc(C(=O)c2ccc(OC)cc2)c(Cl)c1Cl
Agent: Br
Solvent: O
Product: CC(Oc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl)C(=O)O

Procedure:
A mixture of 19.34 g. of ethyl 2,3-dichloro-4-(4'-methoxybenzoyl)phenoxy-α-methylacetate and 330 ml. of 48% hydrogen bromide was rapidly stirred and refluxed for 211/2 hours. The mixture was cooled in an ice bath and diluted with 415 ml. of water, with stirring. The product was filtered and washed with ice water; m.p. 208°-212°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:32]([N:35]1[CH:39]=[CH:38][CH:37]=[N:36]1)[C:33]#[CH:34]>O1CCCC1.C(N(CC)CC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:34]#[C:33][CH2:32][N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCn1cccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#CCn3cccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10) was dissolved in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous triethylamine (20 mL). The solution was degassed and a solution of 1-propargylpyrazol (160 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) was added under inert atmosphere. The resulting solution was degassed and copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added and the mixture was degassed again. The reaction mixture was stirred at ambient temperature overnight; the resulting suspension was filtered through a paddle of silica gel. Silica gel was thoroughly washed with ethyl acetate; the filtrate was evaporated and the residue was dissolved in dichloromethane (30 mL). The solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 80:20) yielding methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]-allyloxy]-2-methylphenoxy]acetate as orange oil.
Reaction SMILES: I(O)(=O)(=O)=O.OC[C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C:23](=[CH:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][C@H:10]1C.[CH3:31][OH:32]>O>[CH3:31][O:32][C:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]2[C@H:13]3[C:23](=[CH:24][CH2:25][C@:26]12[CH3:27])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)=[O:30]
Reactant: CO
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CO
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C

Procedure:
Periodic acid (14.73 g) is dissolved in water (162 ml) and is then slowly added to a stirred solution of 21-hydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione (10.34 g) in methanol (675 ml) at 26°-28°. The reaction mixture is stirred for an additional hour at 20°-25° and then concentrated under reduced pressure with concurrent addition of water (1675 ml). The mixture is cooled and filtered to give 9.94 g of 16°-methylandrosta-4,9(11)-dien-3-one 17β-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]O)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a solution of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (0.250 g) from Example No. 35 in DMF (14 mL) are added DMAP (13 mg), 2,4,6-collidine (0.23 mL), and methanesulfonyl chloride (0.13 mL). The reaction is stirred at rt for 1.5 h and then morpholine (0.60 mL, 6.9 mmol) is added. The reaction is stirred at rt for 18 h. The reaction mixture is poured into water (40 mL). The resulting off-white solid is filtered off and recrystallized from ethanol to yield 0.242 g (81%) of the title compound as an off-white, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:28]([F:31])([F:30])[F:29])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([F:27])[CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:28]([F:31])([F:29])[F:30])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([F:27])[CH2:26][N:25]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:24]4)=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)cc(C2(C(F)(F)F)CC(c3ccc(C4(F)CNC4)cc3)=NO2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
To a solution of 5-(3-chloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 22, 95 mg, 0.2 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.15 mL, 1.1 mmol) and DMAP (5 mg, 0.04 mmol). Contents were stirred for 30 minutes at which time mesyl chloride (25 mg, 0.2 mmol) was added and the reaction was stirred for 18 hours at room temperature. Next, the reaction was concentrated to ˜3 mL under nitrogen purge and injected directly onto a 24 g Redi-Sep column. The crude material was chromatographed eluting from 100% heptane to 30:70 EtOAc:heptane to afford the final product (95 mg, 94%) as a solid. 1HNMR (CDCl3) δ ppm: 7.85 (1H), 7.79-7.77 (3H), 7.72 (1H), 7.64 (2H), 4.50-4.42, (2H), 4.34-4.27 (2H), 4.18 (1H), 3.76 (1H), 3.03 (3H); m/z (Cl) 545 ([M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:22])N)[CH:15]=3)[C:8]2=[O:23])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[C:31]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:22])[CH:15]=3)[C:8]2=[O:23])[CH2:3][CH2:2]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC1CN(c2cccc(C#N)c2)C(=O)N1C1CCN(C(=O)c2ccccc2)CC1
Reaction time: 4 h

Procedure:
The free base of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone (1.99 g, 6.72 mmol) in tetrahydrofuran (50 ml) and triethylamine (1.36 g, 13,44 mmol) was cooled to 0° C. and benzoyl chloride in tetrahydrofuran (10 ml) was added. After 4 h the reaction was complete; the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N HCl and brine, then dried (Na2SO4) and evaporated. The desired product was isolated by flash chromatography using silica get and 2:1 ethyl acetate as eluent. There was obtained 0.63 g of pure 1-(1-benzoylpiperidin-4-yl)-3-(3-cyanophenyl)-5-ethenyl-2-imidazolidinone; LRMS (M+H)+ m/z 401.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[N:10]=1)=[O:5])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([Br:19])=[C:9]([CH3:11])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(C)c(Br)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methyl-thiazole-2-carboxylic acid ethyl ester (171 mg, 1.0 mmol) in acetonitrile (5 ml) is added NBS (180 mg, 1.0 mmol). The reaction mixture is stirred at rt for 2 hr followed by the addition of a second portion of NBS (180 mg, 1.0 mmol). After stirring at rt for 3 hr, the solvent is removed. The resulting residue is purified by PTLC to give the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](NN)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.CCOCC.CCCCCC>[Br:1][C:2]1[S:6][C:5]([S:7]([Br:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: NNS(=O)(=O)c1ccc(Br)s1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: O=S(=O)(Br)c1ccc(Br)s1

Procedure:
To a slurry of 6.43 g (0.025 mol) of 5-bromo-2-thiophenesulfonyl hydrazine and some crushed ice in 100 ml of chloroform was added 8.0 g (0.05) of bromine dropwise with stirring. After the addition was complete and all of the bromine color had disappeared, the chloroform layer was separated and dried over anhydrous magnesium sulfate. The chloroform was removed in vacuo, leaving an orange oil. The oil was dissolved in ether/hexane and cooled to crystallize 3.67 g of the title compound as off-white crystals, mp 48°-50°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45](Br)[CH:46]=2)[NH:41][CH:40]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=3)[CH:46]=2)[NH:41][CH:40]=1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(N)=O)cc1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(-c2ccc3[nH]cc(C[C@H]4CCCN4C(=O)OCc4ccccc4)c3c2)cc1
Yield: 29.5 %

Procedure:
4-carbamoylphenyltri-n-butylstannane (1.833 g, 4,469 mmol) (see Preparation 8) and 3-(1-benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-bromo-1H-indole (1.67 g, 4.05 mmol) (see Preparation 35B) were reacted together in the presence of tri-o-tolylphosphine, triethylamine and palladium (II) acetate using a procedure similar to that described in Example 1. This yielded the title compound as an off-white foam (541 mg). Found: C,71.64; H,6.02; N,8.57; C28H27N3O3. 1/4CH2Cl2 requires: C,71.84; H,5.84; N,8.85%.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:33]3[CH2:32][CH2:31][N:30]([CH:22]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=4)[CH2:35][CH2:34]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(bis(4-chlorophenyl)methylpiperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 82% overall yield. mp 123°-124°. FDMS m/e=510 (M+ of free base). α[D]589 =-8.46 (c=0.89, methanol).