Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23].Cl>C(OCCO)C>[OH:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][NH:19][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CN)CO
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Agent: Cl
Solvent: CCOCCO
Product: CC(C)(CO)CNc1cccc2c1C(=O)c1c(NCC(C)(C)CO)cccc1C2=O
Temperature: 130 °C

Procedure:
A mixture of 1,8-dichloroanthraquinone (13.8 g, 0.05 mol), 3-amino-2,2-dimethylpropanol (20.6 g, 0.20 mol) and 2-ethoxyethanol (100 mL) is heated at about 130° C. for 20 hours. The reaction mixture is drowned into water (1L) and the mixture is acidified with concentrated hydrochloric acid. The product, 1,8 -bis[(3-hydroxy-2,2-dimethylpropyl)amino]anthraquinone, is obtained in an essentially quantitative yield by filtering, washing with water and drying in air. Recrystallization from toluene, followed by filtration, washing with hexane and air drying gives 16.0 g of purified crystalline product. The product may be purified further by recrystallization from methanol. Thin layer chromatography shows that the product contains only one colored component and mass spectrometry analysis is consistent with 1,8-bis[(3-hydroxy-2,2-dimethylpropyl)amino]anthraquinone. The bluish-red product has an absorption maximum at 556 nm and an extinction coefficient (ε) of 12,228 in methylene chloride.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH:10]1[F:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl>[CH3:17][S:18]([O:15][CH:12]1[CH2:13][CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]([F:16])[CH2:11]1)(=[O:20])=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(OS(C)(=O)=O)CC1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorocyclohexanol (500 mg, 2.01 mmol) and TEA (0.56 mL, 4.03 mmol) in DCM (5 mL) was added MsCl (0.28 mL, 3.6 mmol) at 0° C. The reaction mixture was warmed to room temperature, left to stir for 1 h, treated with sodium bicarbonate solution, and neutralized with 1 N HCl. The mixture was extracted with DCM. The combined organics were dried, and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2](=[N:10][OH:11])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[Cl:1][C:2](=[N:10][O:11][C:12](=[O:14])[CH3:13])[C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: O
Product: CC(=O)ON=C(Cl)c1ccc(Cl)cc1
Yield: 77.6 %

Procedure:
To 19 g (0.1 mol) of α-chloro-4-chlorobenzaldoxime prepared above was added 20.6 g (2.0 mol) of acetic anhydride followed by heating on a water bath at a temperature of from 80° to 90°C for about 2 hours. After completion of the reaction, the reaction mixture was poured into water to give pale yellow crystals. The product thus obtained was filtered, dried and recrystallized from ligroin to give 18 g of the desired product as white crystals having a melting point of 76°-77°C. Yield, 77%.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].FC(F)(F)S(O[CH2:34][CH3:35])(=O)=O.CO>C1COCC1>[C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:26][CH2:34][CH3:35])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2
Reaction time: 0.17 h

Procedure:
60 mg (0.16 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in THF (4 ml), and 0.18 ml (0.18 mmol) of N′″-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane) is added. Then 25 μl (0.199 mmol) of ethyl trifluoromethanesulfonate are added to the dark red solution. The decolorized solution is stirred for 10 min and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 35 mg (54% of theory) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:18][C:9]3=[N:10][CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[CH:13]=[C:8]3[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][N:2]1[C:6]2([CH2:18][C:9]3=[N:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]3[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)NC(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)NC(=O)C12Cc1cc(C(=O)O)cnc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (25 mg, 0.091 mmol) in THF (0.5 mL) and H2O (0.3 mL) was added 1 N aqueous lithium hydroxide (0.27 mL, 0.27 mmol). The reaction was stirred at ambient temperature for 1 h, acidified by addition of 1 N hydrochloric acid, and concentrated in vacuo to provide the title compound. MS: m/z=262.1 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 8.31 (s, 1H), 3.55 (m, 2H), 3.44 (d, 1H, J=18.3 Hz), 3.42 (d, 1H, J=17.6 Hz), 2.72 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH2:19][CH2:18]1.Cl>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1
Reactant: ClCCCN1CCN(c2ccccc2Cl)CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: Cl
Product: O=C1CCCc2c(OCCCN3CCN(c4ccccc4Cl)CC3)cccc21
Yield: 78 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-chlorophenyl)-piperazine; yield 78.0% of theory; m.p. of the hydrochloride (recrystallized from water) 248°-250°C;
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][CH:10]=1.[C:25](Cl)(=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1>[CH2:26]([C:25]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][CH:10]=1)=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
{circle around (1)}: A solvent comprising 1.1 g of triethylamine and 5 g of toluene was added dropwise to a mixture comprising 2.28 g of benzyl 4-hydroxybenzoate, 2.33 g of n-tridecanoic chloride and 15 g of toluene in 30 minutes while cooling it with ice. After finishing adding dropwise, the mixture was stirred at room temperature for 3 hours. After finishing the reaction, deposited salts were filtered off, and the filtrate was neutralized with ½ N hydrochloric acid and washed with water. Then, toluene was distilled off under reduced pressure, and the resultant residue was recrystallized from ethanol, whereby 3.52 g of benzyl 4-n-dodecylcarbonyloxybenzoate was obtained in the form of a colorless crystal.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])[N:23]4[N:22]=3)=[C:16]([O:38][CH3:39])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[N:23]2[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][C:16]=3[O:38][CH3:39])=[N:22]2)=[CH:27][CH:28]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Yield: 95.6 %

Procedure:
4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (650.00 mg, 1.227 mmol) was treated with trifluoroacetic acid (0.473 mL, 6.136 mmol) in methylene chloride (3 mL) at room temperature until complete reaction of starting material was observed by hplc analysis of reaction mixture. The reaction was quenched with minimum amount of saturated aqueous sodium carbonate, and was extracted extensively in dichloromethane. The combined organic extracts were dried over MgSO4 and then filtered. Evaporation of solvent under reduced pressure afforded [7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine as a yellow foam (504 mg, 96%) which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:14]([O:34]C)([O:16][C@@H:17]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20]C)=[O:19])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:14]([OH:34])([O:16][C@@H:17]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([OH:20])=[O:19])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)OP(=O)(OC)[C@H](C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
A methanol (1 ml) solution of the methyl (S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(methoxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoate (9.7 mg) obtained in the above step (a) was added with potassium carbonate (5.7 mg), and the mixture was stirred at room temperature for 3 hours. The mixture was acidified with hydrochloric acid and the organic substances were extracted with ethyl acetate. The extract was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate to obtain (S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoic acid (3.1 mg, 34%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 491 (M+H).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]2[CH3:21].CN([CH:25]=[O:26])C>C1COCC1.C(OCC)(=O)C.O>[CH3:21][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH:25]=[O:26])[CH:13]=2)[NH:17][N:16]=1
Reactant: CN(C)C=O
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ccc(C=O)cc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
To an Argon flushed flask of anhydrous THF (81 mL) cooled to −78° C. was added a 1.7M solution of tert-butyllithium in n-pentane (27 mL, 45.6 mmol). After stirring the solution at −78° C. for 15 minutes, a solution of 5-Bromo-3-methyl-1H-indazole (3 g, 14.2 mmol) in THF (42 mL) was added dropwise such that the temperature of the solution did not exceed −70° C. After stirring the solution at −78° C. for 30 minutes, anhydrous DMF (3.15 g, 43.09 mmol) was added dropwise. The reaction mixture was then stirred at −78° C. for 30 minutes, warmed to room temperature and stirred for 1.5 hours. The reaction mixture was cooled down to 0° C. and it was added carefully water (36 mL) and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (heptane/EtOAc 6:4 v/v) to afford white solid (1.6 g, 70%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CCCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 5-hexynoate (109 mg, 0.87 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (179 mg, 0.62 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and Cul (15 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 15 h to yield (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester. (Yield 78 mg, 35%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[CH:10][C:9]2=[O:24])([O-])=O.O.[SH-].[Na+]>CO.O>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)=[CH:10][C:9]2=[O:24]
Reactant: O=c1cc(-c2cccc(C(F)(F)F)c2)oc2c([N+](=O)[O-])cccc12
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: Nc1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Yield: 87.4 %

Procedure:
8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one 2 (300 mg, 0.90 mmol) was taken up in 10 mL of MeOH. Sodium hydro sulfide hydrate (250 mg, 4.5 mol) was added as a solution in 4 mL of H2O. The reaction mixture was stirred under reflux for 45 min. It was then cooled to room temperature and concentrated under reduced pressure. The resulting aqueous mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 240 mg of 178. MS (ESI) calcd for C16H10F3NO2: 305.07. found: 306 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[C:17]=1[O:24][CH3:25].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=CC(OC)=CC=1C(C1C=C(OC)C=C(OC)C=1)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([O:24][CH3:25])[C:18]=2[OH:22])=[O:7])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COc1cccc(OC)c1OC
Agent: COc1cc(OC)cc(C(=O)c2cc(OC)ccc2OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2O)c1
Yield: 50.4 %

Procedure:
3,5-Dimethoxybenzoyl chloride (5.19 g, 25.87 mmol), 1,2,3-trimethoxybenzene (4.35 g, 25.87 mmol) in anhydrous methylene chloride (40 ml), and aluminum chloride (3.79 g, 28.45 mmol) were treated in the same manner as described above for the synthesis of (2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give (3,5-dimethoxy-phenyl)-(2-hydroxy-3,4-dimethoxy-phenyl)-methanone as a yellow solid (4.15 g, 50%); 1HNMR (CDCl3) δ 12.36 (s, 1H, OH), 7.42 (d, J=9 Hz, 1H, Ar), 6.75 (d, J=2 Hz, 2H, Ar), 6.64 (t, J=2 Hz, 1H, Ar), 6.47 (d, J=9 Hz, 1H, Ar), 3.94 (s, 6H, 2OCH3), 3.84 (s, 6H, 2OCH3); 13C NMR (CDCl3) δ 200.4, 160.7, 158.9, 158.0, 140.1, 136.9, 130.3, 114.6, 107.0, 103.8, 102.9, 60.9, 56.3, 55.7; Anal. Calcd. For C17H8O6: C, 64.14; H, 5.70. Found: C, 64.29; H, 5.42; N, <0.05. The product was carried over to the next step.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[F:16]>CS(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([C@@H:17]2[CH2:4][C@H:18]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: CCOC(=O)C=Cc1ccc(F)c(Br)c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(Br)c1
Temperature: 50 °C

Procedure:
Under argon, 381 mg (9.52 mmol) of sodium hydride (60% in paraffin oil) were initially charged in 20 ml of DMSO, and 2.1 g (9.52 mmol) of trimethylsulphoxonium iodide were added in one portion at RT. After the evolution of gas had ceased, 2.0 g (7.3 mmol) of ethyl 3-(3-bromo-4-fluorophenyl)acrylate, dissolved in 10 ml of DMSO, were slowly added dropwise. The reaction mixture was heated at 50° C. overnight, then cooled to RT and, without further work-up, purified by flash chromatography on silica gel (mobile phase isohexane/ethyl acetate 100:1). This gave 907 mg (43% of theory) of the target product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH3:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:29]=[C:30]=[O:31])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH3:12])[CH:19]2[CH2:20][CH2:21][N:22]([C:30]([NH2:29])=[O:31])[CH2:23][CH2:24]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cnc(CN(C2CCNCC2)C(C)c2ccccn2)c(C)c1
Solvent: CC(C)O
Product: Cc1cnc(CN(C2CCN(C(N)=O)CC2)C(C)c2ccccn2)c(C)c1
Yield: 90.7 %

Procedure:
To a solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(1-pyridin-2-yl-ethyl)-amine (194 mg, 0.60 mmol) in 2-propanol (3 mL) was added trimethylsilyl-isocyanate (85 μL, 0.63 mmol). The resultant solution was stirred at room temperature overnight then concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) gave COMPOUND 262 (200 mg, 88%) as a white solid. 1H NMR (CDCl3) δ 0.96-1.02 (m, 1H), 1.45-1.49 (m, 4H), 1.52-1.86 (m, 2H), 2.26 (s, 3H), 2.27 (s, 3H), 2.53-2.62 (m, 1H), 2.71-2.80 (m, 1H), 2.89-2.96 (m, 1H), 3.77-3.97 (m, 5H), 4.37 (s, 2H), 7.10-7.25 (m, 2H), 7.39 (d, 1H, J=7.8 Hz), 7.57-7.62 (m, 1H), 8.19 (br s, 1H), 8.51 (d, 1H-J=3.9 Hz); 13C NMR (CDCl3) δ 13.61, 15.79, 16.16, 27.90, 28.13, 42.22, 42.27, 49.35, 52.87, 55.61, 119.60, 121.54, 129.51, 130.57, 133.80, 136.93, 144.14, 146.25, 152.72, 156.04, 160.52; ES-MS m/z 368 (M+H). Anal. Calcd. For C21H29N5O.0.8H2O: C, 66.05; H, 8.08; N, 18.34. Found: C, 65.9281; H, 7.73; N, 18.18.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:35])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:69]([O:71][C:72]([N:74]1[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]1)=[O:73])[CH3:70]>CN(C=O)C.ClCCl>[CH2:69]([O:71][C:72]([N:74]1[CH2:75][CH2:76][N:77]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:35])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH3:34])[CH2:78][CH2:79]1)=[O:73])[CH3:70]
Reactant: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 225 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid in 4 ml DMF were added 0.32 ml DIPEA, 177 mg HATU and 0.07 ml 1-ethoxycarbonyl-piperazine. After stirring for 1 h it was diluted with dichlormethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].O=[C:18]1[CH:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][S:20][CH2:19]1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:18]2[CH2:19][S:20][CH2:21][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COC(=O)C1CSCC1=O
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Product: CCOC(=O)c1cc(NC(=O)NC2=C(C(=O)OC)CSC2)ccc1Cl

Procedure:
using ethyl 2-chloro-5-ureidobenzoate and methyl 3-oxotetrahydrothiophene-4-carboxylate there is obtained ethyl 2-chloro-5-{3-[4-(methoxycarbonyl)-2,5-dihydro-thien-3-yl]ureido}-benzoate
Reaction SMILES: C([CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)#N.[C:20](=[O:23])(O)[O-:21].[Na+]>S(=O)(=O)(O)O.O>[C:20]([CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)([OH:21])=[O:23]
Reactant: O=C([O-])O
Reactant: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
1-Cyano-2-(2,4-Dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol (4 g, 13.9 mmole) was dissolved in 40% aqueous sulfuric acid (100 ml) and heated in an oil bath at 100°-110° C. for 18 hours. The solution was then cooled, diluted with water (200 ml), and rendered alkaline by the slow addition of solid sodium bicarbonate. The mixture was then extracted several times with ethyl acetate (3×100 ml.) and the aqueous phase was rendered acidic (pH 3) by the addition of dilute orthophosphoric acid. The aqueous phase was then extracted with ethyl ether (3×150 ml), the combined ether extracts were washed once with water, and then dried over magnesium sulfate. Evaporation of the ether gave the title compound as a pale yellow solid, 2.7 g, (62%), m.p. 158°-159° C.