Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:8]=2)[CH2:3]1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[N:8]=2)[CH2:3]1
Reactant: COc1ccccc1Br
Reactant: Cn1c(N2CC[C@@H](N)C2)nc(-c2ccncc2)cc1=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccccc1N[C@@H]1CCN(c2nc(-c3ccncc3)cc(=O)n2C)C1
Yield: 29.7 %

Procedure:
A solution of 2-((R)-3-aminopyrrolidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.20 g, 0.74 mmol), 2-bromoanisole (0.13 g, 0.74 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.061 g, 0.059 mmol), sodium tertbutoxide (0.10 g, 1.03 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.11 g, 0.18 mmol) in toluene (12 ml) and dioxane (2 ml) was stirred for 19 hours at 90° C. The solvent was evaporated off under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate/methanol=5/1) to afford 2-[(R)-3-(2-methoxyphenylamino)pyrrolidin-1-yl]-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.083 g, 29%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:11])=O)=[C:6]([CH:8]=1)[NH2:7].[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:11])(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CS(=O)c1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 21.4 %

Procedure:
Following General Procedure B, the title compound (52 mg, 21%) was prepared from 5-chloro-2-(methylsulfinyl)aniline (Intermediate 2) (120 mg, 0.635 mmol) and 3,4-dichlorobenzene-1-sulfonyl chloride (156 mg, 0.635 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:35][NH2:36].CO>CC(O)CC>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:9]2[S:8][C:6]3=[N:7][C:2]([NH:36][CH3:35])=[CH:3][N:4]=[C:5]3[CH:10]=2)=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: CN
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Solvent: CCC(C)O
Solvent: CO
Product: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Yield: 12 %

Procedure:
A solution of 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.049 mmol, 24 mg) and methylamine 33% in MeOH (0.049 mmol, 500 μL, 4.61 mg) in butan-2-ol (500 μL) was stirred at 150° C. for 5 h. The reaction mixture was concentrated under reduced pressure and purified with HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(methylamino)thieno[2,3-b]pyrazine-6-carboxamide (96a) (3 mg, 12%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.24 (s, 3H), 2.89 (d, J=4.7 Hz, 3H), 7.28 (d, J=8.2 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.62 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.83 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.11 (s, 1H), 8.25 (s, 1H), 10.08 (s, 1H), 10.33 (s, 1H). (m/z)=485 (M+H)+.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10].C([O:16][C:17]([C:19]1[C:20]([S:34][CH2:35][CH3:36])=[N:21][C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)=O)C.CCCCCC>C1(C)C=CC=CC=1.O>[CH2:35]([S:34][C:20]1[C:19]([C:17]([NH:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([F:5])[CH:7]=2)=[O:16])=[C:28]([OH:29])[C:27]2[C:22](=[CH:23][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:25][CH:26]=2)[N:21]=1)[CH3:36]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)c1c(SCC)nc2cc(C(F)(F)F)ccc2c1O
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(O)c1C(=O)NCc1cccc(F)c1
Temperature: 80 °C
Yield: 72.4 %

Procedure:
5.8 ml (11.6 mmol, 2M in toluene)trimethyl aluminium and 1.5 g (11.6 mmol) 3-fluorobenzylamine were added in succession to a solution of 1.0 g (2.9 mmol) 2-(ethylthio)-4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in toluene (18 ml) and the mixture was then heated for 2 h at 80° C. Then it was diluted with water and extracted with EE. The organic phase was washed with 1M hydrochloric acid, water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 17:3) of the residue yielded 0.9 g (2.1 mmol, 73%) 2-(ethylthio)-N-(3-fluorobenzyl)-4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:7][C:6](=[O:8])[CH:5]([C:9](=O)[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:4](=[O:31])[O:3]1.C(O)(=O)C.[BH4-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[O:3][C:4](=[O:31])[CH:5]([CH2:9][C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:6](=[O:8])[O:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)CC1C(=O)OC(C)(C)OC1=O
Reaction time: 0.08 h

Procedure:
(S)-tert-Butyl 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)propan-2-ylcarbamate in 100 mL DCM was cooled to −5° C. Acetic acid (4.45 g, 74.1 mmol) was added in one portion. The resulting mixture was stirred for 5 minutes and sodium borohydride (0.637 g, 16.8 mmol) was added portion-wise over 40 minutes. After stirring for another 40 minutes, the reaction mixture was washed with brine (3×150 mL) and water (2×100 mL). The organic layer was dried over MgSO4. After removing the solvent, the desired product compound (2.5 g, 83%) was obtained as a white solid. LCMS (API-ES) m/z (%): 447.0 (100%, M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([OH:9])[CH2:3]1.C1C=CC=CC=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C.O>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1
Reactant: CC1CC(C)CC(O)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CC1CC(=O)CC(C)C1
Yield: 81.5 %

Procedure:
128 g of 3,5-dimethyl-cyclohexanol and 500 ml of benzene are added to a round flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. While stirring and cooling there is now slowly added dropwise thereto a mixture of 119 g of sodium dichromate, 500 ml of water, 162 ml of concentrated sulphuric acid and 50 ml of glacial acetic acid. Thereby the temperature should not exceed +10° C. The mixture is stirred at this temperature for a further 3 hours and then the organic phase is separated. The aqueous phase is diluted with 130 ml of water and extracted with benzene. The combined organic phases are washed neutral and concentrated. The residue is distilled over a Widmer column and gives 102.7 g of 3,5-dimethyl-cyclohexanone.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH:22]([CH3:23])[CH3:21])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)NCC1CCNC1
Solvent: CC#N
Product: CC(C)NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A suspension of 1.1 g (3.9 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.4 g (10 mmole) of N-(2-propyl)-3-pyrrolidinemethanamine and 50 ml of acetonitrile was refluxed for 2 hours. The precipitate was removed by filtration, washed with acetonitrile, ether, and dried 221° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[O:45][C:46]([F:49])([F:48])[F:47]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([C:41]2[CH:42]=[CH:43][C:44]([O:45][C:46]([F:49])([F:48])[F:47])=[C:39]([F:38])[CH:40]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1ccc(OC(F)(F)F)c(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(OC(F)(F)F)c(F)c2)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 3-fluoro-4-trifluoromethoxyphenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]#[N:9].[CH2:10]([NH:12][NH2:13])C>C(O)C>[CH3:10][N:12]1[C:8]([NH2:9])=[C:3]2[C:2]([CH2:7][CH2:6][CH2:5][CH2:4]2)=[N:13]1
Reactant: CCNN
Reactant: N#CC1CCCCC1=O
Solvent: CCO
Product: Cn1nc2c(c1N)CCCC2

Procedure:
A solution of 2-oxocyclohexanecarbonitrile 120 (10 g, 81.2 mmol) and ethyl hydrazine 119 (3 equiv, 14.6 g) in 150 mL of absolute ethanol was refluxed for 20 hrs and was concentrated on rotavapor to dryness. The crude product was recrystallized from methanol to afford the desired product 124. (Reference for the preparation of compound 124: J. Am. Chem. Soc. 1959, 81, 2448-2452)
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)(=[O:28])=[O:27])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 2-thiophenesulfonyl chloride (530 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(2-thiophenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (759 mg).
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:14][NH:15][O:16][CH3:17].O>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CNOC
Reactant: CCCCCCCCCC(=O)O
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC(=O)N(C)OC
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
Decanoic acid (4 g, 23.2 mmol) was dissolved in an anhydrous dichloromethane solution (80 mL), and 1,1-carbonyldiimidazole (4.5 g, 27.9 mmol) was then added to the solution, followed by stirring for 1.5 hours. Subsequently, N,O-dimethylhydroxyamine hydrochloride (2.7 g, 27.9 mmol) was added to the reaction solution, and the obtained mixture was further stirred for 3 hours. After addition of distilled water, the reaction solution was extracted with dichloromethane two times. Anhydrous magnesium sulfate was added to the organic layer to dry it, and the resultant was filtrated and was then concentrated. The obtained residue was purified using column chromatography (hexane:ethyl acetate=8:1), so as to obtain N-methoxy-N-methyldecanamide (4.8 g, 97%) as an amide body in the form of a colorless transparent liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:22]=[C:21]([CH3:23])[C:14]2[N:15]=[C:16]([CH2:18][CH2:19][CH3:20])[NH:17][C:13]=2[CH:12]=1.[C:24]([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39]([C:44]([OH:46])=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:34][CH:33]=1>[Cl-].C[N+](CCCC)(CCCC)CCCC.C1(C)C=CC=CC=1>[CH3:20][CH2:19][CH2:18][C:16]1[N:17]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]([C:44]([O:46][CH3:24])=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)[C:13]2[C:14](=[C:21]([CH3:23])[CH:22]=[C:11]([C:3]3[N:2]([CH3:1])[C:6]4[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:4]=3)[CH:12]=2)[N:15]=1
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2[nH]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccccc1-c1ccc(CBr)cc1
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 87.5 °C
Reaction time: 6 h
Yield: 72.3 %

Procedure:
1,7′-dimethyl-2′-propyl-1H,3′H-[2,5′]bibenzoimidazolyl (BIM) (4 g), Aliquat® 175 (1.36 ml), K2CO3 (8.19 g), and toluene (50 ml) were added to a 250 ml round bottom flask equipped with a magnetic stirring bar and reflux condenser. The mixture was heated to reflux (about 85-90° C.) until a clear brown organic solution was obtained. 4′bromomethyl-biphenyl-2-carboxylic acid (BMBP) methyl ester (4.5 g) in toluene (24 ml) was added to the clear brown organic solution to form a reaction mixture. The reaction mixture was stirred for about 6 hrs then cooled by ice bath and filtered forming a cooled reaction mixture. The cooled reaction mixture was then extracted twice with water (20 ml), dried over MgSO4, and evaporated forming telmisartan methyl ester (5.02 g), which is about a 69% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.3 g (1.6 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (route 15, step a) in 3 mL DCM at 0° C. were added 0.33 mL (2.4 mmol) triethylamine and 0.19 mL (2.4 mmol) methanesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for 3 hours. 10 mL DCM was added and the mixture was washed with H2O (3×15 mL). The organic phase was dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3 to 6:4).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH3:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[P:17]([Cl:20])(Cl)Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[P:17]([Cl:20])([O:16][C:6]1[C:7]([CH3:15])=[CH:8][C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])[O:16][C:6]1[C:7]([CH3:15])=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)Cl
Reactant: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1OP(Cl)Oc1c(C)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
890.3 g (4 mol) of 2,4-di-tert-butyl-6-methylphenol, 4.2 g of dimethylformamide and 170.0 g of xylene are introduced into a four-neck flask which has been flushed with nitrogen and is fitted with a thermometer, dropping funnel, reflux condenser and distillation attachment. 274.9 g (2 mol) of phosphorus trichloride are added dropwise with stirring over the course of 1.5 hours at a temperature of 50° C. The reaction mixture is warmed to 130° C. and refluxed at this temperature for 1 hour. The reaction mixture is kept at 120° C. for 1 hour under a vacuum of 0.15 bar. Xylene is subsequently removed by distillation under a greater vacuum. After the vacuum has been broken using nitrogen, 959.5 g (1.9 mol) of the title compound are obtained as supercooled, yellow-orange, clear melt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])/[C:15]/3=[CH:22]\[C:23]2[NH:24][CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1)([O-])=O.O.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])/[C:15]/3=[CH:22]\[C:23]2[NH:24][CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:5]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc([N+](=O)[O-])cc3)cc2/C1=C/c1ccc[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C#Cc2ccc3c(c2)/C(=C/c2ccc[nH]2)C(=O)N3)cc1

Procedure:
To a solution of (Z)-1,3-dihydro-5-(4-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (45 mg, 0.13 mmol) (from Example 89) in 1 mL of a 10% water in methanol solution and 0.5 mL THF was added zinc dust (145 mg, 2.21 0 mmol) followed by ammonium chloride (25 mg, 0.47 mmol). The reaction was heated at gentle reflux for 4 hours, at which time the reaction mixture was filtered through a pad of Celite® (Fisher Scientific) and rinsed thoroughly with ethyl acetate. The resulting solution was diluted with 5 mL water and the product was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The resulting powder was recrystallized from EtOAc/hex to give (Z)-5-(4-aminophenyl)ethynyl-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 24 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.C(C1C=C2[C:23](=CC=1)[O:22][C:21](C)(C)[CH2:20]C2)(=O)C.[O-:28]Cl.[Na+].[OH-].[Na+]>>[CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([O:22][CH2:21][CH3:20])=[O:28])[CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2ccccc2O1
Reactant: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc2c(c1)CCC(C)(C)O2

Procedure:
Reaction Scheme 6B discloses a synthetic route to specific preferred benzopyran (chromene) compounds of the invention where with reference to Formula 1 the Z group is also CONH (amide derivatives). In accordance with this scheme, dihydrocoumarine (Compound 213) is subjected to a Grignard reaction with methyl magnesium chloride followed by heating a tertiary alcohol intermediate with acid, to provide 2,2-dimethylchroman (Compound 214). Compound 214 is converted into 6-acetyl-2,2-dimethylchroman (Compound 215) in a Friedel--Crafts reaction, and the latter is oxidized with NaOCl in the presence of sodium hydroxide and thereafter esterified to give ethyl 2,2-dimethylchroman-6-carboxylate (Compound 216). Compound 216 is treated with bromine in glacial acetic acid to give ethyl 8-bromo-2,2-dimethylchroman-6-carboxylate (Compound 217). Compound 217 is oxidized with chromium trioxide to form a ketone function in the 4-position of the chroman ring and yield ethyl 8-bromo-2,2-dimethyl-4-chromanone-6-carboxylate (Compound 218). Reaction of Compound 218 with the Grignard reagent made from 4-bromotoluene, and subsequent heating with p-TSOH to complete dehydration of the intermediate tertiary alcohol, provides ethyl 8-bromo-2,2-dimethyl-4-tolyl-4(2H)-chroman-6-carboxylate (Compound 219). Saponification of Compound 219 with base gives the corresponding free carboxylic acid, 8-bromo-2,2-dimethyl-4-tolyl-4(2H)-chroman-6-carboxylic acid (Compound 220). Compound 220 is condensed with ethyl 2-fluoro-4-aminobenzoate and ethyl 2,6-difluoro-4-aminobenzoate, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and of 4-dimethylaminopyridine (DMAP) to provide ethyl 2-fluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoate (Compound 221) and ethyl 2,6-difluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoate (Compound 222), respectively. Saponification of Compounds 221 and 222 yields the corresponding free carboxylic acids, 2-fluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoic acid (Compound 204) and 2,6-difluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoic acid (Compound 205), respectively. ##STR14##
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH2:31][CH3:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CC#N
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O

Procedure:
Methanesulfonic anhydride (0.6 g, 3.4 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol) and acetonitrile (200 ml). A precipitate formed within a few minutes. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The fractions were separated and the organic fraction was dried (MgSO4), filtered and concentrated to yield the crude product as a white solid. Recrystallization from methyl acetate provided N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a white crystalline solid, m.p. 195.1–196.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=7.4 Hz, 1H), 7.61 (dd, J=8.3, 1.2 Hz, 1H), 7.50 (dt, J=7.5, 1.1 Hz, 1H), 7.26 (dt, J=7.5, 1.2 Hz, 1H), 6.99 (t, J=5.7 Hz, 1H), 6.44 (broad s, 2H), 4.52 (t, J=7.5 Hz, 2H), 3.02–2.86 (m, 7H), 1.82 (m, 4H), 1.62 (m, 2H), 1.46 (q, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3348, 3299, 3152, 2952, 2931, 2869, 1642, 1584, 1530, 1480, 1323, 1155, 1142, 1094, 982, 765 cm−1; MS (EI) m/e 389.1889 (389.1885 calcd for C19H27N5O2S); Anal calcd for C19H27N5O2S: C, 58.59; H, 6.99; N, 17.98. Found: C, 58.26; H, 6.64; N, 17.69