Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:16]1([CH3:25])[C:17]([N:22]=[C:23]=S)=[CH:18][CH:19]=[CH:20][CH:21]=1>C(O)C.[Pd]>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[O:1][C:2]2[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: Cc1ccccc1N=C=S
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(Nc3ccccc3C)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
In ethanol (20 ml) was dissolved methyl 3-hydroxy-4-nitrophenylacetate (1.00 g, 4.74 mmol), followed by the addition of 5% palladium/carbon (500 mg). Under stirring at room temperature, the mixture was subjected to catalytic hydrogenation for 15 hours. After filtration of the reaction mixture through Celite to remove the insoluble matter, 2-tolyl isothiocyanate (765 μl, 5.69 mmol) was added to the filtrate while stirring at room temperature. The reaction mixture was stirred for 15 hours. After addition of mercuric oxide (yellow) (1.72 g, 7.94 mmol), the mixture was heated under reflux for 5 hours under stirring. The reaction mixture was then cooled to room temperature. After filtration of the reaction mixture through Celite under reduced pressure, the solvent was distilled off under reduced pressure from the filtrate. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (10:1) eluate fractions, the title compound (1.18 g, 84%) was obtained as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24]>>[C:23]([C:25]1([C:28]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:22][CH:21]=2)=[O:29])[CH2:27][CH2:26]1)#[N:24]
Reactant: Nc1ccc(CCCCCCCCCc2ccccc2)cc1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCCCc3ccccc3)cc2)CC1
Yield: 93.7 %

Procedure:
General procedure E was used to convert 2.56 mmol of 17 and 3.84 mmol of 1-cyanocyclopropanecarboxylic acid to 2.40 mmol (94%) of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.[NH:10]1[CH2:20][CH2:19][CH:13]([C:14](OCC)=[O:15])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.CN1CCCC1>O>[CH2:8]([C:5]1[N:4]=[N:3][C:2]([N:10]2[CH2:20][CH2:19][CH:13]([CH2:14][OH:15])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH3:9]
Reactant: CCc1ccc(Br)nn1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(N2CCC(CO)CC2)nn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1.67 g (0.011 mol) of 3-bromo-6-ethylpyridazine was added to 1.5 mL (10 mmol) ethyl isonipecotate and 3.5 mL (20 mmol) diisopropylethylamine and 5 mL N methylpyrrolidine (NMP). This mixture was heated to 140° C. for 4 hours. Upon cooling 100 mL of water was added to the mixture and the contents were extracted with methylene chloride then washed twice with water and once with brine and the solvent evaporated in vacuo. The resulting oil was eluted through a short silica gel plug with 80% ethyl acetate and 20% hexanes and dried in vacuo. This intermediate was taken up in 25 mL THF and was exposed to 3-fold excess lithium aluminum hydride with stirring under nitrogen for 1 hour. The reaction was chilled on ice and quenched by dropwise addition of water. The slurry was dried, treated with charcoal and filtered yielding 6-ethyl-3-(4-hydroxymethyl-1-piperidinyl)pyridazine (Formula IV: R1 =C2H5 ; Y=CH2 ).
Reaction SMILES: COC(=O)C=CC1C2N(C3C=CC=CC=3)C=[N:11][C:10]=2C=C(C(F)(F)F)C=1.CN1[CH2:32][CH2:31][N:30]([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)[CH2:29]C1>>[C:10]([CH2:32][CH2:31][N:30]([CH3:29])[C:33](=[O:55])[CH:34]=[CH:35][C:36]1[C:44]2[N:43]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:42]=[N:41][C:40]=2[CH:39]=[C:38]([C:51]([F:54])([F:52])[F:53])[CH:37]=1)#[N:11]
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: CN(CCC#N)C(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Yield: 5 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford the title compound as a white solid (5.6 mg, 5%), m/z 399.0 (M+H)+.
Reaction SMILES: C(O)C.[CH3:4][C:5]1([CH3:23])[C:9]([CH3:11])([CH3:10])[O:8][B:7]([C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([CH3:20])=[O:19])=[CH:14][CH:13]=2)[O:6]1.[BH4-].[Na+]>O>[CH3:11][C:9]1([CH3:10])[C:5]([CH3:4])([CH3:23])[O:6][B:7]([C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([OH:19])[CH3:20])=[CH:14][CH:13]=2)[O:8]1
Reactant: CC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Into ethanol (5.3 mL), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetone (530 mg, 1.92 mmol) synthesized in Reference Example 4 (4a) was dissolved, to which sodium borohydride (94 mg, 2.50 mmol) was added at 0° C., followed by stirring at room temperature for 30 minutes. To this reaction liquid, water was added, followed by extraction with dichloromethane. The resulting organic layer was dried over sodium sulfate and filtered, and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-70:30, V/V) to give the desired title compound (483 mg, yield 91%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.O.S(OCC)(O[CH2:20][CH3:21])(=O)=O.[OH-].[Na+]>COCCOC>[CH2:20]([CH:2]([OH:1])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:21]
Reactant: O=[N+]([O-])c1cc(NCCO)ccc1O
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CCC(O)CNc1ccc(O)c([N+](=O)[O-])c1
Temperature: 5 °C

Procedure:
39.6 g (200 mmol) 4-(2-hydroxyethylamino)-2-nitrophenol is added to a mixture of 150 ml water and 15 ml 1,2-dimethoxyethane. 33.9 g (220 mmol) diethyl sulfate is added dropwise at an internal temperature of 60° C. so that the pH of the solution is maintained between 6 and 8 by simultaneous dropwise addition of 10% sodium hydroxide (ca. 62 ml). After complete reaction, the solution is filtered through a pleated filter and cooled with stirring to 5° C. The product is allowed to crystallize.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>O1CCOCC1>[Cl:12][CH2:13][C:14]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C(CCl)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of p-chlorobenzoic hydrazide (11.2 g) in dioxane (100 ml) was added chloroacetyl chloride (6 ml). The resulting mixture was refluxed for three hours, cooled to room temperature and filtered. The resulting solid was washed with ethyl ether and dried to yield N'-chloroacetyl-4-chlorobenzoic hydrazide as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH:28]([C:30]1[N:31]=[CH:32][N:33]2[CH:37]=[CH:36][S:35][C:34]=12)=[O:29].O>C(OCC)C.C1COCC1>[Si:10]([O:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:28]([OH:29])[C:30]2[N:31]=[CH:32][N:33]3[CH:37]=[CH:36][S:35][C:34]=23)[CH:7]=[N:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Reactant: O=Cc1ncn2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cncc(C(O)c2ncn3ccsc23)c1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
A solution of 2.49 g of 5-bromo-3-(t-butyldimethylsilyloxymethyl)pyridine in 25 ml of dry diethyl ether was cooled to −85° C. under an argon atmosphere, and 5.56 ml of a 1.57 N n-butyllithium/hexane solution was added dropwise to the cooled solution over a period of 10 min. The mixture was stirred at that temperature for 30 min, and a solution of 881 mg of 7-formylimidazo[5,1-b]thiazole in 20 ml of dry THF was then added thereto, followed by further mixing at the same temperature for 30 min. Water was added to the reaction solution. The mixture was extracted three times with chloroform. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1) to give 803 mg of 7-[[5-(t-butyldimethylsilyloxymethyl)pyridin-3-yl]hydroxymethyl]imidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[C:20]3[C:21]4([CH2:24][O:25][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:22]4)=[CH:12][CH:13]=1)=[O:6])([CH3:4])[NH2:3].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:27](=[O:29])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[C:20]4[C:21]5([CH2:24][O:25][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH2:23][CH2:22]5)=[CH:12][CH:13]=2)[C:5]1=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 139.9 %

Procedure:
To a solution of 2-methyl-N1-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]alaninamide (Reference Intermediate 219, 34 mg) in dry dichloromethane (6 mL) TEA (0.070 mL, 0.501 mmol) was added and the mixture was cooled to 0° C. A solution of triphosgene (13.38 mg, 0.045 mmol) in dry dichloromethane (2 mL) was slowly added and the reaction mixture was stirred for 1 hour at the same temperature. The reaction was quenched with water (3 ml) and two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column SNAP and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title as a white solid (23 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][NH:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH3:2].Br[CH2:19][CH2:20][CH2:21]Cl>C1(C)C(C)=CC=CC=1>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:7]2=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]2[CH2:21][CH2:20][CH2:19]1)[CH3:17]
Reactant: CCN(CC)CCNc1nc2ccccc2[nH]1
Reactant: ClCCCBr
Solvent: Cc1ccccc1C
Product: CCN(CC)CCN1CCCn2c1nc1ccccc12

Procedure:
Heat at reflux for 12 hours a mixture of 1.16 g (5 mmol) of 2-(2-diethylaminoethylamino) benzimidazole and 0.6 ml (5 mmol) of 1-bromo-3-chloropropane in 10 ml of xylene. After cooling, the xylene is decanted off and the residual oil is treated with petroleum ether. Evaporate the remaining petroleum ether and treat with ammonium hydroxide. Extract with chloroform. The combined organic phases are concentrated and passed over a column of alumina eluted with chloroform. The evaporation of the solvent allows the title compound to be obtained.
Reaction SMILES: [C:1](=[O:42])([O:11][C:12]1[C:13]([CH3:41])=[C:14]2[C:19](=[C:20]([CH3:23])[C:21]=1[CH3:22])[O:18][C:17]([CH3:40])([CH2:24][CH2:25][CH2:26][CH:27]([CH3:39])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:16][CH2:15]2)[O:2][CH2:3][CH:4]1[CH2:8][O:7]C(C)(C)[O:5]1.O1CCCC1.CO.Cl>CCOCC>[C:1](=[O:42])([O:11][C:12]1[C:13]([CH3:41])=[C:14]2[C:19](=[C:20]([CH3:23])[C:21]=1[CH3:22])[O:18][C:17]([CH3:40])([CH2:24][CH2:25][CH2:26][CH:27]([CH3:39])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])[CH2:16][CH2:15]2)[O:2][CH2:3][CH:4]([OH:5])[CH2:8][OH:7]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCC1COC(C)(C)O1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC(O)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 90.8 %

Procedure:
A mixture comprising 3.9 g of 2,2-dimethyl-1,3-dioxolan-4-ylmethyl 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanyl carbonate, 15 ml of tetrahydrofuran, 5 ml of methanol and 5 ml of 2 N hydrochloric acid was stirred and heated under reflux for 3 hours. The reaction mixture was dissolved in ether, successively washed with water, an aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane : ethyl acetate=3.5:1.5) to thereby give 3.3 g of the title compound as a pale yellow, viscous liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:38]=[CH:37][C:27]3[NH:28][C:29]([CH3:36])([CH3:35])[CH:30](CCC)[S:31][C:26]=3[CH:25]=2)[C:9]2[CH:23]=[CH:22][C:12]3[NH:13][C:14]([CH3:21])([CH3:20])[CH:15](CCC)[S:16][C:11]=3[CH:10]=2)=C[CH:3]=1.CC1(C)C(C)(C)NC2C=CC(CC3C=C(CC4C=CC5NC(C)(C)C(C)(C)SC=5C=4)C4NC(C)(C)C(C)(C)SC=4C=3)=CC=2S1>>[CH3:20][C:14]1([CH3:21])[NH:13][C:12]2[CH:22]=[CH:23][C:9]([C:8]3([C:24]4[CH:38]=[CH:37][C:27]5[NH:28][C:29]([CH3:35])([CH3:36])[CH2:30][S:31][C:26]=5[CH:25]=4)[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]3)=[CH:10][C:11]=2[S:16][CH2:15]1
Reactant: CCCC1Sc2cc(C(c3ccc(Cl)cc3)c3ccc4c(c3)SC(CCC)C(C)(C)N4)ccc2NC1(C)C
Agent: CC1(C)Nc2ccc(Cc3cc(Cc4ccc5c(c4)SC(C)(C)C(C)(C)N5)c4c(c3)SC(C)(C)C(C)(C)N4)cc2SC1(C)C
Product: CC1(C)CSc2cc(C3(c4ccc5c(c4)SCC(C)(C)N5)CCCCC3)ccc2N1

Procedure:
1-(4-chlorophenyl)-1,1-di-(3,3-dimethyl-2-propyl-2,3-dihydro-4H-1,4-benzothiazin-7-yl)-methane ##STR7## 2,2-di-(10a-methyl-1,2,3,4,4a,10a-hexahydrophenothiazin-7-yl)-propane ##STR8##1-(2,2,3,3-tetramethyl-2,3-dihydro-4H-1,4-benzothiazin-7-yl)-1-[2,2,3,3-tetramethyl-5-(2,2,3,3-tetramethyl-2,3-dihydro-4H-1,4-benzothiazin-7-yl-methyl)-2,3-dihydro-4H-1,4-benzothiazin-7-yl]-methane.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[CH2:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([N:14]([C:2]([NH:1][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CN=C=O
Reactant: CCCCNc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from ethyl isocyanatoacetate and 1-[4-(butylamino)phenyl]-4-piperidineone (which was obtained in Example 364) according to the procedure of Example 366 as a pale brown solid; MS (ES) m/z: 376.5 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(OCC)(=O)C>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][N:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CCCCCBr
Reactant: COc1ccc(S(=O)(=O)NCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN(CCO)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 24 h
Yield: 81.8 %

Procedure:
Part A: To a solution of 2.0 g (8.6 mmol) of N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide from Example 1 in 20 mL of anhydrous DMF, was added 3.58 g (25.9 mmol) of powdered potassium carbonate and then 1.96 g (13 mmol) of 1-bromopentane. After 24 hours, ethyl acetate and water was added, the organic layer separated and washed 3×s with brine, dried with sodium sulfate, filtered and stripped to afford 2.3 g of crude product. This was chromatographed on 150 g of silica gel using 20%-50% ethyl acetate/hexane to afford 2.12 g of the desired N-(hydroxyethyl)-N-pentyl-4-methoxybenzenesulfonamide, m/e=302 (M+H).
Reaction SMILES: O[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.P(Cl)(Cl)([Cl:21])=O.O>CN(C)C=O>[Cl:21][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate (15 g) in dimethyl-formamide (170 ml) was added dropwise phosphorus oxychloride (7.4 ml) under ice-cooling. The reaction solution was heated at 100° C., and stirred for 2 hours. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give methyl 4-chloro-5-nitro-2-(trifluoromethyl)benzoate (14.78 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11]2)=[CH:6][C:5]=1[NH2:21])([O-:3])=[O:2].CC1(C)[O:28][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=O)[O:24]1>>[C:32]([C:31]1[CH:30]=[C:29]([C:27](=[O:28])[CH2:26][C:25]([NH:21][C:5]2[CH:6]=[C:7]([N:10]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:11]3)[CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:24])[CH:36]=[CH:35][CH:34]=1)#[N:33]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: Nc1cc(-n2ccc(-c3ccccc3)c2)ccc1[N+](=O)[O-]
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3ccc(-c4ccccc4)c3)ccc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-nitro-5-(3-phenyl-pyrrol-1-yl)-phenylamine (Example F6) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as an orange solid (267 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[N:24]1([C:30]2[CH:31]=[C:32]([NH2:42])[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:35]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCOCC1.C(OCC)(=O)C>[N:24]1([C:30]2[CH:31]=[C:32]([NH:42][C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=3)[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:35]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(-c2ccccc2)cc(N2CCOCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccnc(Nc2cc(-c3ccccc3)cc(N3CCOCC3)c2)n1
Temperature: 100 °C

Procedure:
2-Chloro-4-(trifluoromethyl)pyrimidine (23 μL, 0.19 mmol) and TsOH—H2O (29.9 mg, 0.157 mmol) were added to a solution of 5-(morpholin-4-yl)biphenyl-3-amine (40 mg, 0.157 mmol) in dioxane (1.5 mL) and then the reaction mixture was heated to 100° C. for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 (aq) followed by brine. The aqueous layers were extracted with ethyl acetate, then the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided N-[5-(morpholin-4-yl)biphenyl-3-yl]-4-(trifluoromethyl)pyrimidin-2-amine as a light yellow solid. MS ESI calc'd. for C21H20F3N4O [M+H]+ 401, found 401. 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J=4.9 Hz, 1H); 7.61 (d, J=7.6 Hz, 2H); 7.56 (s, 1H); 7.50-7.34 (m, 4H); 7.23 (s, 1H); 7.05 (d, J=4.9 Hz, 1H); 6.88 (s, 1H); 3.92 (t, J=4.5 Hz, 4H); 3.29 (t, J=4.5 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([CH:11]=[CH2:12])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36]([O:38][CH3:39])=[O:37])[CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:14].[C:40](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:40][N:31]([S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[CH2:12])[C:6]=4[C:2]=3[CH3:1])=[O:14])=[CH:21][CH:20]=2)=[CH:23][CH:24]=1)(=[O:30])=[O:29])[C@H:32]([C:36]([O:38][CH3:39])=[O:37])[CH:33]([CH3:35])[CH3:34]
Reactant: C=Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N(C)[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of 0.077 g (0.14 mmol) of the product of Example 96, Step 2, methyl N-[(4′-{[(3-methyl-4-vinyl-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate, in 1 mL of DMF, 0.05 g of potassium carbonate were added, followed by 0.018 mL of iodomethane. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to provide 0.1 g of methyl N-methyl-N-[(4′-{[(3-methyl-4-vinyl-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate. Yield 63.4%. MS: 561 (M+H)+.
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].CI.[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]>C1COCC1>[CH3:1][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Cs2CO3 (7 g; 21.5 mmol) followed by CH3I (10 g; 70 mmol) was added to a solution of 4-hydroxy-1-indanone (5.0 g; 34 mmol) in THF (30 mL) and the mixture was stirred at RT for 60 h. The reaction mixture was filtered and concentrated, and the crude product was purified using flash chromatography (SiO2; methylene chloride) to yield 3.1 g (56%) of the sub-title substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:20])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(F)cc1
Temperature: 35 °C
Yield: 99 %

Procedure:
Into a suitable reactor is charged 4-fluorophenylacetic acid (122.5 kg, 795 mol), N,N-dimethylformamide (0.37 kg, 5.1 mol), and toluene (490 kg). Oxalyl chloride (105.2 kg, 829 mol) is added at a rate to maintain the temperature at about 35° C. The solution is stirred for at least 7 hours at about 25° C., typically affording a solution of about 22.1 wt % 4-fluorophenylacetyl chloride (99% yield as determined by HPLC assay).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[O:20][C:19]3[CH:18]=[C:17]([OH:21])[CH:16]=[C:15]([OH:22])[C:14]=3[C:12](=[O:13])[CH:11]=2)=[CH:7][C:8]=1[OH:9].[CH2:23](Br)[C:24]#[CH:25]>>[CH2:23]([O:22][C:15]1[C:14]2[C:12](=[O:13])[CH:11]=[C:10]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:4][C:3]#[CH:8])[CH:7]=3)[O:20][C:19]=2[CH:18]=[C:17]([O:21][CH2:7][C:6]#[CH:5])[CH:16]=1)[C:24]#[CH:25]
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1O
Reactant: C#CCBr
Product: C#CCOc1cc(OCC#C)c2c(=O)cc(-c3ccc(OC)c(OCC#C)c3)oc2c1

Procedure:
30 g of diosmetin are alkylated with propargyl bromide under the conditions of Example 3 to yield, after recrystallisation from isopropanol, 32 g of the title compound in pure form, m.p.: 196° C.