Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[Se:15][C:14]=1[C:22]([NH2:24])=[O:23].CN(C=O)C.[OH-].[Na+]>>[C:18]([C:16]1[Se:15][C:14]([C:22]([NH2:24])=[O:23])=[C:13]([NH:12][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: Clc1ncnc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ncnc3ncccc23)c(C(N)=O)[se]1

Procedure:
The reaction of 4-chloropyridino[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a yellow color solid, mp 222-224° C. IR (KBr) vmax 3310, 3180, 2961, 1616, 1572, 1383, 1332, 1316, 1280, 1245, 1226, 1090 cm−1; 1H NMR (400 MHz, CDCl3+DMSO-d6): δ 9.10 (1H, dd, J=4.4, 1.6 Hz), 8.96 (1H, s), 8.81 (1H, s), 8.55 (1H, dd, J=8.4, 1.6 Hz), 7.54 (1H, dd, J=8.4, 4.4 Hz), 6.50 (2H, br s), 1.48 (9H, s); 13C NMR (100 MHz, CDCl3+DMSO-d6): 168.6, 168.3, 158.6, 157.9, 156.5, 155.8, 146.1, 131.3, 121.9, 121.1, 111.7, 110.3, 36.8, 32.2; LC-MS (negative ion mode): m/z 372, 374 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][NH:17][C:18]3=[O:23])=[C:4]([O:31]C)[C:3]=1[F:33].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:29])([CH3:30])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:25])[F:26])[CH:11]2[NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][NH:17][C:18]3=[O:23])=[C:4]([OH:31])[C:3]=1[F:33]
Reactant: COc1c(C(C)(C)CC(O)(C=Nc2cccc3c(=O)[nH]ccc23)C(F)(F)F)ccc(Cl)c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2cc(Cl)c(F)c(O)c21
Temperature: 25 °C
Yield: 31.5 %

Procedure:
80.3 mg (0.166 mmol) of (rac.) 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-1(2H)-one is mixed at room temperature with 1.7 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two and one-half hours at room temperature. The reaction mixture is mixed with ice, and then saturated sodium bicarbonate solution is added in drops (pH 8). After ethyl acetate is added, and after ten minutes of vigorous stirring at room temperature, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 24.6 mg (31.6%) of the desired compound is isolated.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Li].[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH3:16])[C:9]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1)=[O:18].[NH4+].[Cl-]>O1CCCC1>[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH3:16])[C:9]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1)([OH:18])[CH3:5]
Reactant: [Li]C
Reactant: COc1cc(C)c(C(=O)c2ccc(OC)c(C(C)C)c2)c(C)c1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C)c(C(C)(O)c2ccc(OC)c(C(C)C)c2)c(C)c1
Reaction time: 2 h
Yield: 43 %

Procedure:
To anhydrous cerium chloride (1.185 g, 4.80 mmol) dry tetrahydrofuran (15 mL) was added with stirring under argon and stirring was continued for 2 hours at room temperature. The resultant suspension was then cooled at -78° C., and 3.43 mL of methyllithium (1.4M in diethylether) was added with stirring, whereupon the color of the suspension turned from white to yellow. After maintaining the same temperature for 30 minutes, (2,6-dimethyl-4-methoxyphenyl)-(3-isopropyl-4-methoxyphenyl) methanone (10) (1 g, 3.20 mmol) in tetrahydrofuran (5 mL) was added and the mixture was stirred for 3 hours at -78° C. and for 2 hours at 0° C. The reaction mixture was treated with sat. NH4Cl solution, filtered through Celite, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), evaporated, and the residue was purified by flash column chromatography (silica gel, 97:3 hexane/ethylacetate) to give 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethanol (12) (450 mg, 1.37 mmol, 43%); 1HNMR (CDCl3) δ 1.20 (dd, 6H), 1.58 (s, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.30 (heptet, 1H), 3.82 (s, 3H), 3.88 (s, 3H), 6.50 (s, 1H), 6.60 (s, 2H), 6.80 (d, 1H), 7.06 (d, 1H).
Reaction SMILES: [N:1]#[C:2][NH2:3].Cl.C([NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:11])(C)(C)C>O>[C:14]([N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:2]([NH2:3])=[NH:1])=[CH:18][CH:19]=1)[C:10]([NH2:9])=[O:11])([CH3:19])([CH3:15])[CH3:13]
Reactant: CC(C)(C)NC(=O)NCc1ccc(N)cc1
Reactant: N#CN
Agent: Cl
Solvent: O
Product: CC(C)(C)N(Cc1ccc(NC(=N)N)cc1)C(N)=O
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 142.1 %

Procedure:
Cyanamide (100 g, 2.4 mol) was placed in a 500 mL round bottom flask and heated to 60-65° C. until the material completely melted. N-tert-butyl-N'-4-aminobenzylurea hydrochloride, (25.3 g, 97.8 mmol) was then added directly to the liquid cyanamide and the resulting yellow solution was stirred at 60-65° C. an additional two hours. Water (100 mL) was subsequently added to the solution followed by cooling to room temperature. The aqueous solution was washed with ethyl ether (1 L) followed by back extraction of the organic phase with water (2×100 mL). The combined aqueous layers were again washed with ethyl ether (500 mL) and the aqueous solution cooled in an ice water bath followed by basification with aqueous sodium hydroxide (10M, 100 mL). The resulting insoluble oil slowly crystalized and was collected by filtration. The material then was washed with water and dried in vacuo to give N-tert-butyl-N-4-guanidinobenzylurea (18.3 g, 70.8%) as a colorless crystalline solid.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH3:19].S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH3:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[O:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]=[O:2]
Reactant: COC(OC)c1ccccc1COc1cc(C)ccc1C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(OCc2ccccc2C=O)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
The crude 2-(2,5-dimethylphenoxymethyl)benzaldehyde dimethyl acetal (73.7 g) obtained in Example 9, 22 mL of xylene and 150.0 g of a 35 wt % sulfuric acid aqueous solution were mixed. The resultant mixture was stirred at 60° C. for 2 hours. To this was added 187 mL of xylene, and the resultant mixture was separated at the same temperature. The resultant organic layer was cooled down to room temperature, then, washed with 75.0 g of a 5 wt % sodium hydroxide aqueous solution, then, with 150 mL of water. The resultant organic layer was concentrated under reduced pressure, to give 60.5 g of crude 2-(2,5-dimethylphenoxymethyl)benzaldehyde as yellow solid. Content: 97.1 wt % Yield: 97.1% (based on 2-(2,5-dimethylphenoxymethyl)benzal chloride)
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:14]=[C:15]([CH3:20])[NH:16][C:17]=1[CH:18]=[O:19].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[Cl:12][C:13]1[N:14]=[C:15]([CH3:20])[NH:16][C:17]=1[C:18]([OH:5])=[O:19]
Reactant: Cc1nc(Cl)c(C=O)[nH]1
Reactant: O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1nc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
A solution of sodium chlorite (1.4 g, 15.3 mmol) and sodium dihydrogen phosphate monohydrate (1.2 g, 8.7 mmol) in water (3.3 mL) was added to a stirred solution of 4-chloro-2-methyl-1H-imidazole-5-carbaldehyde (0.308 g, 2.1 mmol), 2-methyl-2-butene (9.3 mL of a 2M solution in THF, 18.6 mmol), and tert-butanol (1.2 mL) in THF (4.7 mL). The reaction mixture was stirred at RT for 6 h. The aqueous phase was separated and extracted with EtOAc (4×10 mL). The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was triturated with diethyl ether to provide the title compound (0.168 g, 50%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.98 (br. s., 1H), 12.88, (br. s., 1H), 2.26 (s, 3H). ES-LCMS: m/z 160.9 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][CH:5]([N:7]([CH2:9][C@@H:10]2[C@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH2:29])[O:11]2)[CH3:8])[CH2:4]1.[C:30]([C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[NH2:29][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[C:26]=1[N:27]=[CH:28][N:20]2[C@H:12]1[C@@H:13]2[O:17][C:16]([CH3:19])([CH3:18])[O:15][C@@H:14]2[C@@H:10]([CH2:9][N:7]([CH3:8])[CH:5]2[CH2:4][CH:3]([CH2:2][NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)=[O:42])[CH2:6]2)[O:11]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CN)C1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CNC(=O)Nc2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 9-((3aR,4R,6R,6aR)-6-(((3-(aminomethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine in DCM (4 ml) was added 1-tert-butyl-4-isocyanatobenzene (37 mg). The mixture was stirred at RT for 1 h. The mixture was concentrated and purified via preparative-TLC (DCM:MeOH=10:1) to give the title compound (55 mg, Yield 45% for two steps). ESI-MS (m/z): 578.3[M+1]+.
Reaction SMILES: [CH2:1]([N:4](C)[CH2:5][C@@H:6]([CH3:34])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([Cl:33])[CH:20]=1)=[N:11][CH:12]=[N:13]2)C=C>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:33][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[CH:17][C:8]=3[O:7][C@H:6]([CH3:34])[CH2:5][NH:4][CH3:1])[N:13]=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 15 %

Procedure:
5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine was heated in acetonitrile/water in the presence of chlorotris(triphenylphosphine)rhodium (I) using an analogous procedure to that described below in Example 4-11 (preparation of starting materials) to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine in 15% yield; Mass spectrum M+ 450.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[CH:13]>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.[Cu](I)I>[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[C:13][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)CC#Cc1cncc(N)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a degassed solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol) and N,N-dimethylprop-2-yn-1-amine (1.57 mL, 14.6 mmol) in TEA (26 mL) were added bis(triphenylphosphine)palladium(II) chloride (0.203 g, 0.29 mmol) and copper iodide (0.110 g, 0.58 mmol). The reaction mixture was allowed to stir under an atmosphere of argon at 80° C. for 14 h. The reaction mixture was allowed to cool to rt and then filtered through Celite. The filter pad was washed with EtOAc and the filtrate was concentrated. The residue was purified by column chromatography to give 5-[3-(dimethylamino)prop-1-yn-1-yl]pyridin-3-amine (0.55 g, 54%).
Reaction SMILES: Cl.S(=O)(=O)(O)O.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=1.[NH3:16]>C(O)C>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[NH:15])=[N:12][CH:13]=1
Reactant: N
Reactant: N#Cc1ccc(N)cn1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N=C(N)c1ccc(N)cn1
Reaction time: 0.5 h

Procedure:
Dry HCl gas (generated by adding concentrated HCl dropwise in concentrated sulphuric acid), was passed through a solution of 5-amino-2-cyanopyridine (2.5 g, 20.9 mmol) in ethanol (50 mL) till pH of the reaction mixture was 2. The reaction mixture was stirred for 30 minutes, followed by addition of ethanolic ammonia solution till the pH was alkaline and was stirred for 24 hours at room temperature. The reaction mixture was filtered and the residue was washed with ethanol (3×100 mL). The filtrate was combined and ethanol was removed under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, 13% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[Na].C(O)(=O)C.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]>>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:19][C:18]([O:21][CH2:22][CH3:23])=[O:20])[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CCOC(C)=O
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)C(OCC)OCC
Yield: 44.8 %

Procedure:
To a solution of ethyl diethoxyacetate (24.5 g) in ethyl acetate (12.5 g), metallic sodium (4.2 g) was added, and the resultant mixture was refluxed for about 1.5 hours. The reaction mixture was made acidic with 50% acetic acid and extracted with ether. After removal of the ether from the extract by distillation, the residue was subjected to fractional distillation to give ethyl diethoxyacetoacetate (13.6 g) as a colorless, transparent oil boiling at 84° C./4 mmHg.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH2:19][C:12]1=2>>[CH2:2]([O:9][NH:10][C:21]([NH:20][CH:16]1[C:13]2[CH:14]=[CH:15][S:11][C:12]=2[CH2:19][CH2:18][CH2:17]1)=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C=NC1CCCc2sccc21
Agent: Cl
Product: O=C(NOCc1ccccc1)NC1CCCc2sccc21

Procedure:
In the manner described in Example 6, O-benzyl hydroxyamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate are allowed to react to afford 1-(benzyloxy)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is recrystallized from 95% ethyl alcohol-methyl isobutyl ketone. The product melts at 96.5° C. to 99° C.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:12]=[N:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][CH3:21])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][C@@H:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:12]=[N:13]/[C:14]1[C:15]([NH:20][CH3:21])=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNc1ccccc1/N=C/[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNc1ccccc1/N=C/[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{(S)-1-Benzyl-2-[(E)-2-methylamino-phenylimino]-ethyl}-carbamic acid benzyl ester (0.075 g, 0.20 mmol) was dissolved in absolute ethanol (7 mL) and treated with 10% palladium on carbon (0.040 g). The resulting suspension was shaken under 60-65 psi H2 at room temperature for 16 h. The suspension was filtered and the filter cake washed with MeOH (−100 mL), and the combined filtrates concentrated in vacuo to give N-[(S)-2-Amino-3-phenyl-prop-(E)-ylidene]-N′-methyl-benzene-1,2-diamine, as a light yellow oil (0.052 g, approximately quantitative yield): ES+ LC/MS m/e 238 (M+H), RT=3.12 min.
Reaction SMILES: C(OC(Cl)=O)C.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[Br:17].CN(C)CC1C=CC=CC=1>C(OCC)C>[F:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][C:9]=1[Br:17]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: CCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Solvent: CCOCC
Product: OCc1ccc(F)c(Br)c1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
10.8 g of chloroformic acid ethyl ester were added dropwise to a solution of 20.8 g of 95% pure 4-fluoro-3-bromo-benzoic acid and 13.5 g of dimethylbenzylamine in 200 ml of diethyl ether at 0° C. Stirring was continued at 0° to 20° C. for 1 hour and the hydrochloride which had precipitated was then filtered off. After adding 0.1 g of triethylbenzylammonium bromide, a solution of 7.6 g of sodium borohydride in 50 ml of water was added dropwise to the filtrate at 20° C. The reaction mixture was subsequently stirred at 20° C. for 3 hours and was then acidified with dilute hydrochloric acid. The ether phase was separated off and washed once with 30 ml of saturated sodium bicarbonate solution. The ether phase was then concentrated. 17.3 g (93.4% of theory) of 4-fluoro-3-bromobenzyl alcohol were thus obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OCc2ccccc2)c1
Reaction time: 6 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (300 mg, 1.7 mmol) was dissolved in DMF (8.5 ml) and treated with benzyl bromide (200 μl, 1.7 mmol). Cs2CO3 (610 mg, 1.87 mmol) was then added and the reaction mixture stirred at room temp. for 6 hours. The mixture was filtered and washed with DMF (3×10 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: CC1(C)C(B2OC(C)(C)C(C)(C)O2)=CCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:54][C:55]1([CH3:80])[C:59]([C:60]2[CH:65]=[C:64]([C:66](OCC)=[O:67])[CH:63]=[CH:62][C:61]=2[C:71]2[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[CH:73][C:72]=2[F:79])=[CH:58][CH2:57][CH2:56]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CN(C=O)C.O.C1COCC1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:54][C:55]1([CH3:80])[C:59]([C:60]2[CH:65]=[C:64]([CH2:66][OH:67])[CH:63]=[CH:62][C:61]=2[C:71]2[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[CH:73][C:72]=2[F:79])=[CH:58][CH2:57][CH2:56]1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCCC2(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CCC=C1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A reaction mixture of compound B.6 (1.80 g, 5.80 mmol), 2-(5,5-dimethylcyclopent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (B.3) (1.40 g, 6.4 mmol), S-Phos (0.48 g, 1.20 mmol), tripotassium phosphate (3.10 g, 15.0 mmol) and palladium acetate (0.13 g, 0.58 mmol) in DMF (10.0 mL) and water (1.0 mL), was purged with N2 three times. The resulting mixture was heated at 100° C. overnight. EtOAc (120 mL) was added, and the mixture was washed with brine (25×2 mL). The organic layer was dried with MgSO4. The residue was purified by CombiFlash® chromatography (silica gel, eluent with hexane/EtOAc, 9/1) to give Suzuki coupling product as an intermediate, ethyl 2-(5,5-dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-carboxylate. MS ESI (pos.) m/e: 369.1 (M+H)+. To a solution of ethyl 2-(5,5-dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-carboxylate (1.00 g, 3.0 mmol) in THF (10.0 mL), was slowly added LAH, (1.0M solution in diethyl ether, 4.0 mL, 4.0 mmol) at 0° C. After the addition, the reaction mixture was stirred at 40° C. for 1.5 hours, and then at room temperature for 2 hours. A mixture of water (0.22 mL) in THF (2.0 mL) was slowly added and then 15% sodium hydroxide (0.22 mL) was added at 0° C. Finally, water (0.65 mL) was added at room temperature. The solid was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by CombiFlash® chromatography (silica gel column, eluent with hexane/EtOAc, 90/10 to 70/30) to give the title compound B.7. 1H NMR (400 MHz, CDCl3) δ ppm. 7.24 (s, 2H), 7.09-7.21 (m, 1H), 6.84-6.96 (m, 1H), 6.68-6.72 (m, 2H), 5.43 (s, 1H), 4.65 (s, 2H), 3.66 (s, 3H), 2.17 (td, 2H), 1.77 (b, 1H), 1.58 (t, 2H), 0.78 (s, 6H). MS ESI (pos.) m/e: 309.1 (M−HO)+, 345.2 (M+H3O)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[N+](=[CH2:18])=[N-]>CCOCC>[CH3:18][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)CCCCCCC1CCCC1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCCCCCC1CCCC1=O

Procedure:
A 2.14 g. portion of 7-(2-oxocyclopentyl)-heptanoic acid was dissolved in 20 ml. of anhydrous ether and cooled to 0° C. in an ice bath. The stirred solution was then treated with ethereal diazomethane in about 1 ml. portions to control gas evolution until the yellow color persisted and bubbling was slow. The excess reagent was then blown off with a stream of nitrogen and the solvent evaporated at the rotovap. The residual oily ester was dried in vacuo over phosphorous pentoxide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(C)cc1
Yield: 77 %

Procedure:
Prepared according to the procedure described for Example 121 using 4-methylbenzenesulfonyl chloride (2.06 g, 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.053 g); m.p. 200-202° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:12]=[CH:11][C:10](=[O:13])[C:9]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si](C)(C)C)[CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[N:8]2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-]>C1COCC1>[C:25]([C:21]1[CH:20]=[C:19]([N:15]2[C:14]([C:9]3[C:10](=[O:13])[CH:11]=[CH:12][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[N:8]=3)=[CH:18][CH:17]=[N:16]2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C[Si](C)(C)C#Cc1cccc(-n2nccc2-c2nn(-c3ccncc3)ccc2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(-n2nccc2-c2nn(-c3ccncc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of 1-Pyridin-4-yl-3-[2-(3-trimethylsilanylethynyl-phenyl)-2H-pyrazol-3-yl]-1H-pyridazin-4-one (example 98, 33 mg, 0.08 mmol) is dissolved in THF (1 ml). Tetrabutylammoniumfluoride trihydrate (51 mg, 0.16 mmol) is added at 0° C. and the reaction mixture is allowed to warm up to ambient temperature within 15 minutes. Stirring is continued for another 1 hour. The reaction mixture is quenched with water and extracted with ethyl acetate. The solvent is removed and the obtained crude product is purified by chromatography on silica gel using EtOAC/MeOH gradient to obtain 22 mg (81% yield) of the product. MS: M=340.1 (M+H)+