Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:19]1([CH:24]([N:28]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[N:29]2)[CH2:25][C:26]#[N:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.COCCOC.O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:31]3[CH:30]=[N:29][N:28]([CH:24]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][C:26]#[N:27])[CH:32]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(Cl)ncnc21
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 82 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
Into a 50 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (3f, 700 mg, 2.61 mmol), 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 935 mg, 2.97 mmol, 1.13 equiv), 1,2-dimethoxyethane (DME, 10 mL, 96 mmol), water (5 mL, 0.28 mol) and potassium carbonate (K2CO3, 1.82 g, 7.84 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol, 0.010 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 82° C. The reaction mixture was stirred at 82° C. for 6 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (10 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic fractions were washed with aqueous brine (2×25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-50% ethyl acetate/hexane gradient elution) to afford racemic 4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 0.97 g, 1.1 g theoretical, 88.6% yield) as colorless oil, which solidified upon standing at room temperature in vacuo. For 20: 1H NMR (CDCl3, 300 MHz) δ 8.85 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.45 (d, 1H, J=3.8 Hz,), 6.73 (d, 1H, J=3.8 Hz), 6.22 (s, 2H), 4.23 (ddd, 1H, J=10.0, 8.6, 4.0 Hz), 3.10 (dd, 1H, J=17.0, 8.6 Hz), 2.92 (dd, 1H, J=17.0, 4.0 Hz), 2.56 (m, 1H), 2.00-1.25 (m, 8H), 1.12 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421 (M++H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1>COCCOC>[N:10]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][N:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:11]=12
Reactant: Nc1cnccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccncc2n1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
Ethyl bromopyruvate (2.15 g, 11.04 mmol) was added to stirred solution of 2-aminopyrazine (1 g, 10.5 mmol) in 1,2-Dimethoxy ethane (10 mL). The reaction mixture was stirred at 20-35° C. for 2 h. The mixture was then filtered to obtain a solid precipitate which was dried well, dissolved in EtOH (10 mL) and refluxed for 2 h. This mixture was concentrated, diluted with aqueous saturated sodium bicarbonate solution, extracted with chloroform. The chloroform layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using 60-120 silica gel and 60% EtOAc in Hexane as eluent) to afford 450 mg of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:22]>CO.O1CCOCC1>[ClH:22].[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C@H:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]2[OH:1])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Oc1ccc([C@H]2CCNC[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.5 g, 5.1 mmol, E-2 from example 46 step E) in methanol (50 mL) under nitrogen was added 12.8 mL of 4 M HCl in dioxane and the reaction was stirred for 1 h at rt. The mixture was then evaporated under reduced pressure to dryness and the residue was washed twice with 20 mL of diethyl ether. The solid residue was dried under vacuum to give (3R,4R)-4-(4-hydroxyphenyl)-piperidin-3-ol hydrochloride E-2a (950 mg, 4.1 mmol). LCMS (method F) RT: 0.17 min, m/z 194 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.93 (m, 2H) 2.61-2.68 (m, 1H) 2.81-2.93 (m, 1H) 3.21-3.33 (m, 2H) 3.78-3.90 (m, 1H) 6.72 (d, J=8.53 Hz, 2H) 7.00 (d, J=8.53 Hz, 2H) 9.14-9.25 (m, 1H) 9.27-9.44 (m, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:2]=[O:3].[CH3:17][CH:18]([CH3:41])[CH:19]([NH:24][C:25]([C:27]1[S:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=2)=[CH:30][N:31]=1)=[O:26])[C:20]([O:22][CH3:23])=[O:21]>>[CH3:17][CH:18]([CH3:41])[CH:19]([NH:24][C:25]([C:27]1[S:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:3])=[CH:34][CH:33]=2)=[CH:30][N:31]=1)=[O:26])[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccccc3Oc3ccccc3)cc2)s1)C(C)C
Yield: 84 %

Procedure:
The title compound was synthesized analogous to Example 9, using 1-isocyanato-2-phenoxybenzene and intermediate 2. Yield: 84%; 1H NMR (DMSO-d6, 300 MHz): δ 9.53 (s, 1H), 8.73 (d, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 8.27 (dd, 1H), 7.73 (d, 2H), 7.57 (d, 2H), 7.43 (dd, 2H), 7.17 (m, 1H), 7.1 (d, 1H), 7.07 (dd, 2H), 6.98 (d, 1H), 6.86 (d, 1H), 4.32 (m, 1H), 3.68 (s, 3H), 2.28 (m, 1H), 0.94 (d, 6H); MS (ES+) m/z 545 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Br:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].[C:15](OCC)(=[O:17])C>>[F:1][C:2]1[CH:8]=[C:7]([Br:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[N:4]=[C:15]=[O:17]
Reactant: CCOC(C)=O
Reactant: COC(=O)Oc1cc(N)c(F)cc1Br
Product: COC(=O)Oc1cc(N=C=O)c(F)cc1Br
Temperature: 80 °C
Yield: 94 %

Procedure:
A solution of trichloromethyl chloroformate trichloromethyl (15 ml, 125 mmol) in ethyl acetate was charged into a 500 ml-three neck flask equipped with a dropping funnel and distillation apparatus and, a solution of 2-fluoro-4-bromo-5-methoxycarbonyloxyaniline (28.0 g,113 mmol) in ethyl acetate (100 ml) was added dropwise over 20 minutes. After dropping, the mixture was heated at 80° C. and ethyl acetate was removed by distillation. After cooling, carbon tetrachloride (150 ml) was added and the undissolved substances were removed by filtration. The solvent was then removed from the filtrate by distillation under reduced pressure, whereby a brown solid of 2-fluoro-4-bromo-5-methoxycarbonyloxyphenyl isocyanate (29.1 g, yield 94%) was obtained.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][C@@H:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].Cl[C:17]1[O:18][C:19]2[C:20](=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:24][CH:25]=2)[N:21]=1>COCCOC>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:17]2[O:18][C:19]3[C:20](=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:24][CH:25]=3)[N:21]=2)[C@@H:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN[C@@H](CC(C)C)C1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCN1CCN(c2nc3c(C(=O)OC)cccc3o2)[C@@H](CC(C)C)C1
Reaction time: 0.75 h
Yield: 43 %

Procedure:
To a solution of (S)-1-allyl-3-isobutylpiperazine (442 mg, 2.42 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 100 mg, 2.42 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (510 mg, 2.42 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 10:1:0.1 CH2Cl2/CH3OH/concentrated NH4OH) to afford methyl 2-(4-allyl-(S)-2-isobutylpiperazine-1-yl)benzoxazole-4-carboxylate (372 mg, 43%) as a yellow oil. 1H NMR and MS consistent.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=2)[CH2:10][CH:9]1[C:32](=[O:44])[NH:33][C:34]1([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH:35]1[CH:37]=[CH2:38])=[O:7])(C)(C)C.FC(F)(F)S(O)(=O)=O>ClCCl.C([SiH](CC)CC)C>[CH2:42]([O:41][C:39]([C:34]1([NH:33][C:32]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:44])[CH2:36][CH:35]1[CH:37]=[CH2:38])=[O:40])[CH3:43]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Compound 16 (780 mg, 1.29 mmol) was dissolved in dichloromethane (20 mL) and triethylsilane (0.4 mL). Trifluoromethanesulfonic acid was added dropwise at room temperature. The mixture was then left for 2 h at room temperature. Removal of the solvent gave pure title product (700 mg, 99%) MS (M+H)+ 546.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:15].[C-:20]#[N:21].[Na+].Cl>CS(C)=O>[C:20]([CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])#[N:21]
Reactant: [C-]#N
Reactant: O=C1CCCC(=O)C1Cc1ccccc1CCCCl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCc1ccccc1CC1C(=O)CCCC1=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of 22 g (0.079 mol) of 2-[2-(3-chloropropyl) benzyl ]- 1,3-cyclohexanedione 3 and 15.5 g (0.316 mol) of NaCN in 250 ml of dry dimethyl sulfoxide was stirred at 95 ° C for 3 hours. The reaction was filtered while hot to remove NaCl, and the dimethyl sulfoxide was distilled out under high vacuum. The residue was dissolved in 400 ml H2O, filtered through a diatomaceous earth filter aid (celite) to give a red solution and neutralized by the rapid addition of 40 ml concentrated HCl. The precipitate was recrystallized twice from ethyl acetate to give 16 g of the cyanodione, IIa, mp 143° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([F:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][C:29]4([CH2:28][CH2:27][O:26][CH3:25])[CH2:31][CH2:30]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([F:24])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)c(F)c1
Reactant: COCCC1(N)CC1
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4F)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-0.66 (m, 2H) 0.66-0.73 (m, 2H) 1.80 (t, J=6.9 Hz, 2H) 3.14 (s, 3H) 3.39 (t, J=7.1 Hz, 2H) 7.61 (dd, J=8.2, 1.6 Hz, 1H) 7.75 (dd, J=11.9, 1.5 Hz, 1H) 8.14 (d, J=3.0 Hz, 1H) 8.30 (dd, J=8.7, 2.1 Hz, 1H) 8.40 (d, J=8.6 Hz, 1H) 8.56 (t, J=8.0 Hz, 1H) 8.76 (s, 1H) 8.80 (d, J=1.5 Hz, 1H) 13.69 (br. s., 1H). MS m/z 422 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:24]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:24])=[O:18])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CS(C)=O
Product: O=CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
1-(4-Benzyloxy-3-nitrophenyl)-2-bromoethanone (12.6 g) was dissolved in dimethyl sulphoxide (40 ml) and the solution was allowed to stand at room temperature for 3 days. The solution was poured onto ice and the product was collected as the hydrate (8.7 g). τ (d6DMSO) 4.58 (2H, s), 4.33 (1H, s), 2.25-2.65 (6H, m), 2.07 (2H, br), 1.30-1.87 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH2:16][C:17]([NH2:19])=[O:18].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29](=O)[C:30]([O-])=[O:31])=[CH:21]1.C(O[K])(C)(C)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[CH:4][C:3]=1[C:16]1[C:17](=[O:18])[NH:19][C:30](=[O:31])[C:29]=1[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:20][CH:21]=1
Reactant: O=C([O-])C(=O)c1c[nH]c2ccccc12
Reactant: Cc1cc(N2CCN(C)CC2)cc(CC(N)=O)c1Cl
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(N2CCN(C)CC2)cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c1Cl
Temperature: 35 °C
Reaction time: 8 h

Procedure:
2-[2-Chloro-3-methyl-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (211 mg, 0.75 mmol) and 3-indoleglyoxylate (270 mg, 1.35 mmol) are dissolved in THF (5 mL). A solution of 1.0 M tert-BuOK in THF (2.98 mL, 4 eq) is added and the mixture is stirred at 35° C. overnight. The reaction is diluted with AcOEt (20 mL) and washed with H2O (20 mL) and brine (10 mL). The organic phase is dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (AcOEt/AcOH/H2O 7:1:1) to afford the title compound in the form of its acetate salt. 1H NMR (DMSO, 400 MHz) δ 2.16 (s, 3H), 2.31 (s, 3H), 2.32-2.38 (m, 4H), 2.97-3.10 (m, 4H), 6.61 (d, J=8.0 Hz, 1H), 6.71-6.77 (m, 2H), 7.04 (d, J=2.8 Hz, 1H), 7.08 (dd, J=7.4, 7.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 11.05 (br s, 1H), 11.90 (br s, 1H); ES-MS: 435 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][C:28]=1[F:41].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][C:28]=2[F:41])[C:7]1=[O:18]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (2 g), potassium carbonate (1.2 g) and acetonitrile (50 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.3 g, 41%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:3]1[C:4]2[C:10](=[O:13])[C:9]3[C:2](=[CH:3][CH:4]=[CH:5][CH:8]=3)[C:6](=[O:7])[C:5]=2[CH:8]=[CH:9][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: OCc1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Subsequently, in 70 ml of DMF, 3.5 g of the compound (F), 2.4 g of p-chlorobenzyl alcohol and 12 g of potassium carbonate were stirred at 120° C. for 5 hours. After filtration, DMF was removed under reduced pressure, and purification was carried out by column chromatography to yield 2.5 g of the target anthraquinone dye No. 8.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][S:46]([C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1)(=[O:48])=[O:47].NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:53][C:52]4[CH:54]=[CH:55][C:49]([S:46]([CH3:45])(=[O:47])=[O:48])=[CH:50][CH:51]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(S(C)(=O)=O)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(methylsulfonyl)aniline as the aniline component. (15%, MS=534.2 (M+H))
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.Cl[CH:34]([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:23][CH:24]=1)[C:10]([O:17][CH:34]([F:36])[F:35])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12
Reactant: FC(F)Cl
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using {3-[4-(2,2-dimethylpropionyl)benzyl]-8-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy}acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].ClC1C(OC)=CC=C(Cl)C=1N[C:27](=O)[N:28](C)[C:29]1[CH:34]=[C:33](NC2C=CC(N3CCN(C)CC3)=CC=2)[N:32]=[CH:31][N:30]=1>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:33]3[CH:34]=[C:29]([NH:28][CH3:27])[N:30]=[CH:31][N:32]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: COc1ccc(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Product: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 144A but using 4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol) and (6-chloro-pyrimidin-4-yl)-methyl-amine (Example 1) (771 1.81 g, 12.68 mmol, 1.3 eq.). Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR=1.10 min (gradient J); TLC: Rf=0.21 (DCM/MeOH, 93:7).
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12](=[O:42])[C@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:25][CH:24]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C.ClCCl.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>[CH3:10][O:11][C:12](=[O:42])[C@H:13]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:28]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: Cn1cccc(Br)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A solution of 3-bromo-1-methyl-2-pyridone (94 mg, 0.50 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (284 mg, 0.50 mmol) in DMF (3 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3 ×). bis(triphenylphosphine)palladium dichloride (40 mg, 0.057 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 20 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane (20 mL) and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in 1:1 ether:ethyl acetate (20 mL). The solution was washed with water (1×10 mL), 5% potassium fluoride (2×5 mL) and water (1×10 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 25 g of silica gel eluting with 4:6 ethyl acetate:hexane to give N-[(1,1-dimethylethoxyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (64 mg, 33%). LRMS-Electrospray: m/z positive ion, 795 (2M+Na) 409 (M+Na) 387 (M+H). HRMS: Obs. Mass 387.1935. Calcd. Mass 387.1920 (M+H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[Br:6][C:7]1[CH:27]=[CH:26][C:10]([C:11]([CH:13](Br)[CH2:14][C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:16])=[O:12])=[CH:9][CH:8]=1>C(O)C>[C:1]([S:3][CH:13]([C:11](=[O:12])[C:10]1[CH:26]=[CH:27][C:7]([Br:6])=[CH:8][CH:9]=1)[CH2:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])(=[O:4])[CH3:2]
Reactant: O=C(c1ccc(Br)cc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 469 mg. of potassium thioacetate in 10 ml. of ethanol is added 1.76 g. of 1-[3-(4-bromobenzoyl)-3-bromopropionyl]-L-proline (Example 37). The mixture is stirred at room temperature for 18 hours, filtered and the filtrate evaporated to dryness. The residue is dissolved in dichloromethane, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo giving the desired product as 1.68 g. of a white glass.