Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20](O)=[O:21])[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:20]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]3)=[O:21])[CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: OCC1CCCNC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
To a solution of 3-piperidinemethanol (5.0 g, 43.4 mmol), 1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid (9.14 g, 43.4 mmol), and diisopropylethylamine (11.22 g, 86.8 mmol) in dichloromethane (100 mL) at 0° C. was added PyBroP® (22.26 g, 47.8 mmol). The reaction was stirred at 0° C. for 1 h and then at room temperature for 4 h. The reaction mixture was washed successively with water, 1 N HCl, water, sat. sodium bicarbonate solution, and water (100 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol (96:4) to give 5.8 g of the amide 1 as a thick gum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[CH3:11][N:10]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:22]3[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)=[CH:15][C:6]=2[C:7]([CH3:13])([CH3:14])[O:8][C:9]1=[O:12]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccc([N+](=O)[O-])cc3)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-nitrophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z 328 ([M+H]+); MS (ESI) m/z 326 ([M−H]−); Anal. calcd for C17H17N3O4: C, 62.38; H, 5.23; N, 12.84. Found: C, 62.03; H, 5.15; N, 11.41.
Reaction SMILES: [F:1][C:2]([F:33])([CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(C(C)C)CC)(C)C.[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[F:33][C:2]([F:1])([CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:26]
Reactant: BrCc1ccccc1
Reactant: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OCc2ccccc2)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.1 %

Procedure:
To the crude 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (17) (132.1 mmol) in acetonitrile (315 ml), diisopropyl ethylamine (69.0 ml, 369 mmol) and benzyl bromide (47.1 ml, 369 mmol) were added and the mixture was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate (366 ml) and water (280 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (224 ml). The organic layers were combined and washed with 1N-hydrochloric acid (336 ml), saturated sodium bicarbonate water (336 ml) and saturated aqueous sodium chloride (336 ml). After drying with anhydrous magnesium sulfate (51 g), the solution was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2400 g; ethyl acetate:hexane =1:2) to give benzyl 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (18) (74.44 g; 130.9 mmol; yield: 99.1%) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][C:12]1[CH:13]=[C:14]2[C:24]([CH2:25][CH:26]=1)=[C:17]1[NH:18][C:19](=[O:23])[C:20](=[O:22])[NH:21][C:16]1=[CH:15]2.C(N(CC)CC)C>CN(C)C=O>[C:1]1([NH:7][C:8](=[O:9])[NH:11][C:12]2[CH:13]=[C:14]3[C:24]([CH2:25][CH:26]=2)=[C:17]2[NH:18][C:19](=[O:23])[C:20](=[O:22])[NH:21][C:16]2=[CH:15]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1=CCC2=c3[nH]c(=O)c(=O)[nH]c3=CC2=C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1=CCC2=c3[nH]c(=O)c(=O)[nH]c3=CC2=C1)Nc1ccccc1
Reaction time: 8 h

Procedure:
1.92 ml of phenyl isocyanate are added at a temperature in the region of 20° C. to a solution of 1.5 g of 7-amino-1,4-dihydro-5H-indeno [1,2-b]pyrazine-2,3-dione hydrochloride and 2.48 ml of triethylamine in 20 ml of dimethylformamide. After overnight stirring at the same temperature, the precipitate formed is filtered off, washed with water and dried under a partial vacuum (1 mm Hg; 0.13 kPa) at 40° C. to yield 1.4 g of 7-(3-phenylureido)-1,4-dihydro-5H-indeno[1,2-b]pyrazine-2,3-dione in the form of a greenish solid, the melting point of which is above 260° C. (Analysis C18H14N4O3 ; 4.0 H2O; % calculated C: 64.66; H: 4.22; N: 16.76; % found C: 64.4; H: 4.5; N: 16.8; 1H NMR spectrum [250 MHz, (CD3)2SO-d6, δ in ppm]: 3.58 (s, 2H CH2 9); 7.00 (t, J=7.5 Hz, 1H: aromatic H of the phenyl at para with respect to the ureido); 7.30 (t, J=7.5 Hz, 2H: aromatic H of the phenyl at meta with respect to the ureido); 7.50 (d, J=7.5 Hz, 2H: aromatic H of the phenyl at ortho with respect to the ureido); from 7.20 to 7.60 (mt, 2H: H 5 and H 6); 7.72 (s broad, 1H: H 8); 8.80 (s broad, 2H: ArNHCONH); 12.00 and 12.28 (2 unres. comp. 1H each: NHCOCONH).
Reaction SMILES: [C:1]1([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CI.[Cl:23]([O-:27])(=[O:26])(=[O:25])=[O:24].[Na+]>CC(C)=O>[Cl:23]([O-:27])(=[O:26])(=[O:25])=[O:24].[C:1]1([C:11]2[CH:12]=[NH+:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncc(-c3cccc4ccccc34)cc2c1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CI
Product: c1ccc2[nH+]cc(-c3cccc4ccccc34)cc2c1
Reaction time: 10 h

Procedure:
Furthermore, the 3-(1-naphthyl)quinoline (2-2) (70 mg, 0.27 mmol) was dissolved in 10 ml of acetone, and further methyl iodide (130 μl, 2 mmol) was added thereto, which then was stirred for 10 hours. The solvent was removed therefrom and 20 mL of methanol was then added thereto. Subsequently, sodium perchlorate (0.12 g, 1.0 mmol) was added thereto and thereby salt exchange (ion exchange) was performed. Thus, perchlorate of 3-(1-naphthyl)quinolinium ion (quinolinium ion derivative 2) was obtained. The yield amount of the quinolinium ion derivative 2 perchlorate thus obtained was 93 mg and the yield from the 3-(1-naphthyl)quinoline (2-2) was 93%. The instrumental analysis data of this quinolinium ion derivative 2 perchlorate is indicated below.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30]>>[F:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][CH:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:7])[N:9]=[CH:10]2)=[CH:15][CH:14]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(F)c(F)c3)ccc2c1O
Product: CC(NC(=O)c1ncc2cc(Oc3ccc(F)c(F)c3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-50 by reacting 7-(3,4-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (compound of Example A-62 a) with L-alanine in a pressure tube for 3 days at 85° C. MS-(+)-ion: M−1=389.2.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH2:1]([NH:4][C:17]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:18])[C:2]#[CH:3]
Reactant: O=C(Cl)C1CCCC1
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)C1CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
Dissolve propargylamine (1.5 g, 28.07 mmol) in DCM (50 mL), add triethylamine (7.83 mL, 56.15 mmol) and cool the mixture to 0° C. Add cyclopentanecarbonyl chloride (2.5 g, 18.72 mmol) and warm to room temperature. Stir the reaction mixture for 18 h. Wash the mixture with water (3×50 mL) and hydrochloric acid (2N, 50 mL) and dry the organic phase over MgSO4. Remove the solvent in vacuo and triturate the solid with iso-hexane to give the title compound as a fine white powder (1.51 g, 53%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([F:22])[CH:9]=2)=[N:6][CH:7]=1.[Na+].[CH3:24][S:25]([O-:27])=[O:26].[OH-].[Na+].O>CS(C)=O>[F:22][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][N:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Fc1cc(-c2ccc(Br)cn2)ccc1OCc1ccccc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCc3ccccc3)c(F)c2)nc1
Yield: 33.6 %

Procedure:
2-{3-Fluoro-4-[(phenylmethyl)oxy]phenyl}-5-(methylsulfonyl)pyridine (0.168 g, 34%) was prepared as a white solid from 5-bromo-2-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}pyridine (0.50 g, 1.40 mmol), methanesulfinic acid sodium salt (0.72 g, 80%, 5.58 mmol) Cul (0.80 g, 4.19 mmol), NaOH (67 mg, 1.68 mmol) and water (0.4 mL) in DMSO (15 mL) in a manner similar to Example 83, Step 2. The crude product was triturated with hot MeOH containing 5% of CHCl3. 1H NMR (400 MHz, CDCl3): δ 9.14 (d, 1H, J=2.4 Hz), 8.22 (dd, 1H, Ja=8.3 Hz, Jb=2.5 Hz), 7.91 (d, 1H, J=2.2 Hz), 7.90-7.70 (m, 2H), 7.50-7.30 (m, 5H), 7.11 (t, 1H, J=8.6 Hz), 5.23 (s, 2H), 3.13 (s, 3H); LRMS (ESI), m/z 358 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C2C=CC=C(C(F)(F)F)C=2)=[CH:4][C:3]=1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]3[CH:33]=[N:32][CH:31]=[N:30][C:26]=3[NH:27]2)=[CH:23][CH:22]=1.O1CCOCC1.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]3[CH:33]=[N:32][CH:31]=[N:30][C:26]=3[NH:27]2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N)cc1-c1ccc2c(c1)[nH]c1ncncc12
Temperature: 100 °C
Yield: 76.2 %

Procedure:
To N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide (442 mg, 0.990 mmol) was added 1,4-dioxane (2.0 mL) and water (2.0 mL) and sodium hydroxide (790 mg, 19.8 mmol). The resulting mixture was heated to 100° C. until LCMS indicated complete hydrolysis, typically 14-16 hours. The reaction was cooled to ambient temperature and the solvents were removed by evaporation. The residue was washed with water and the remaining solid was recovered by filtration, washed with additional water, and dried under reduced pressure to give the product (207 mg, 76%). 1H NMR (300 MHz, DMSO): δ 9.42 (s, 1H), 8.90 (s, 1H), 8.22 (d, 1H), 7.39 (s, 1H), 7.23 (d, 1H), 6.94 (d, 1H), 6.52 (m, 2H), 4.95 (s, 2H), 2.08 (s, 3H). MS (EI) m/z=275 (M+H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O>[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1F)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.7 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (3.0 g, 15.2 mmol) in dimethylformamide (35 mL) under nitrogen was added potassium carbonate (6.3 g, 45.6 mmol) followed by a solution of the crude 2,4-difluorobenzoylchloride of Step A (22.8 mmol) in dimethylformamide (15 mL). After stirring at room temperature for 20 minutes, the reaction mixture was washed with water and stirred to give a solid which was collected by filtration. The solid was dissolved in chloroform and washed with 1 N sodium hydroxide and brine. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided the title compound (2.6 g) as a white foam which crystallized by sonication from hexane-ethanol, m.p. 161-163° C.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.Cl>C(#N)C.[Cu]Cl>[CH3:1][C:2]([O:6][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)([CH3:3])[C:4]#[CH:5]
Reactant: C#CC(C)(C)O
Reactant: Oc1ccc2ncccc2c1
Agent: Cl[Cu]
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-methyl-3-butyn-2-ol (2.45 mL, 25.1 mmol) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) in acetonitrile (15.5 mL) was stirred 0° C. for 30 minutes, and trifluoroacetic anhydride (3.55 mL, 25.1 mmol) was added dropwise. The resulting mixture was added dropwise to a mixed solution of 6-hydroxyquinoline (2.43 g, 16.7 mmol), copper (I) chloride (8.3 mg, 0.0835 mmol), acetonitrile (15.5 mL) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) at 0° C., and stirred at 0° C. for 3 hours. The resulting solution was acidified with 1 mol/L HCl and extracted with ethyl acetate, and the resulting aqueous phase was neutralized with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1 to 1/3) and the aimed product was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:26]4[C@H:25]([CH3:24])[CH2:29][O:28][C:27]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cn3)CC2)c(C)c1
Yield: 22.3 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 150 and (R)-4-methyloxazolidin-2-one (111 mg) described in Preparation Example 25, the title compound (88 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.Cl.Cl.[CH3:16][O:17][C:18]1[C:19]([N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:16][O:17][C:18]1[C:19]([N:24]2[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:6][CH:7]=3)[CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccnc1N1CCCNCC1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccnc1N1CCCN(Cc2csc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Chloromethyl)-2-phenyl-1,3-thiazole (52 mg, 0.25 mmol), 1-(3-methoxy-pyridin-2-yl)-[1,4]diazepane dihydrochloride (70 mg, 0.25 mmol), and Cesium carbonate (325 mg, 1.0 mmol) were suspended in anhydrous DMF (1.25 mL). The mixture was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc and washed with H2O (3×25 mL), then brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified on silica (CH2Cl2:MeOH+1% NH4OH) to afford the product. 1H NMR (400 MHz, CDCl3) δ 7.94 (m, 2H), 7.79 (dd, 1H, J=1.6, 4.8 Hz), 7.40 (m, 3H), 7.15 (s, 1H), 6.96 (dd, 1H, J=1.4, 8.2 Hz), 6.66 (dd, 1H, J=4.8, 7.6 Hz), 3.93 (s, 2H), 3.80 (s, 3H), 3.71 (m, 4H), 2.98 (t, 2H, J=5.0 Hz), 2.85 (t, 2H, J=5.6 Hz), 2.04 (quin., 2H, J=5.9 Hz). MS (ES) m/z 381.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:17]=[CH:16][N:15]=1>CN(C=O)C>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=1
Reactant: COc1ccccc1-c1ccnc(Cl)c1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccnc(Nc2cccc(CS(N)(=O)=O)c2)c1
Yield: 1.8 %

Procedure:
G2 was prepared from (3-aminophenyl)methanesulfonamide (85 mg, 0.46 mmol) and A1 (100 mg, 0.46 mmol) following the procedure reported for G1 by heating in DMF for 3 hours, and it was obtained as a colorless amorphous solid (3.1 mg, 2%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.79 (s, 3H), 4.15 (s, 2H), 6.73 (bs, 2H), 6.84 (dd, J=5.3 Hz, J=1.5 Hz, 1H), 6.96-6.98 (m, 1H), 7.04 (dt, J=1.0 Hz, J=8.0 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.21-7.25 (m, 2H), 7.33 (dd, J=7.6 Hz, J=1.8 Hz, 1H), 7.36-7.42 (m, 1H), 7.64-7.68 (m, 2H), 8.14 (d, J=5.3 Hz, 1H), 9.08 (s, 1H). MS (ES) C19H19N3O3S requires: 369. found: 370 (M+H)+.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1.[S]>CC(C)=O>[C:1]1([CH:16]=[CH:16][C:1]2[CH:2]=[CH:3][C:4]([C:7]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:8])=[CH:5][CH:6]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Oc2ccccc2)cc1
Agent: [S]
Solvent: CC(C)=O
Product: O=C(Oc1ccccc1)c1ccc(C=Cc2ccc(C(=O)Oc3ccccc3)cc2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 5.9 %

Procedure:
Sixty five g (0.306 mole) of neat phenyl p-toluate were maintained in the temperature range of 280°-310° C. (boiling point) while a slow stream of nitrogen was bubbled in from below the surface (sparged). Sulfur (1.92 g, 0.060 mole) dissolved in more phenyl p-toluate (20 g, 0.099 mole) at 100° C. was added slowly with stirring over a period of 2-3 hours. The heating, stirring and nitrogen sparging were continued an additional four hour and then the mixture was allowed to cool near 80° C. and 100 mL of boiling acetone was added. The suspension was transferred to a larger flask and an additional 400 mL of acetone was added. The suspension was filtered at the boil to yield 3.8 g of diphenyl 4,4'-stilbenedicarboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:21]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8].O.[O-:33][C:34]#[N:35].[K+]>N1C=CC=CC=1>[NH:1]([CH2:2][CH2:3][CH2:4][N:5]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:21]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8])[C:34]([NH2:35])=[O:33]
Reactant: COc1ccc(CCNC(=O)CN(CCCN)c2cc(C)nc(-n3ccnc3)n2)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CCNC(=O)CN(CCCNC(N)=O)c2cc(C)nc(-n3ccnc3)n2)cc1
Temperature: 80 °C

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide (135 mg, 0.32 mmol) (a compound of formula (Yc6)) in pyridine (1.5 mL) was added water (1.5 mL) solution of potassium cyanate (64 mg, 0.76 mmol). The mixture was stirred and heated in an oil bath at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (9:1 CH3CN/NH4OH) to afford 2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide, a compound of formula (Yc9); as a white solid; NMR (DMSO-d6, 90 C) 8.4 (s, 1), 7.8 (s, 1), 7.05 (d, 2), 7.0 (s, 1), 6.75 (d, 2), 6.4 (s, 1), 4.1 (s, 2), 3.7 (s, 3), 3.5 (m, 2), 3.25 (m, 2), 3.05 (m, 2), 2.65 (t, 2), 2.3 (s, 3), 1.7 (m, 2) ppm.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccc2c(c1)CCO2
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: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
2,3-dihydrobenzofuran-5-boronic acid (0.114 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H2O and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (5-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.0762 g in 78% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)CC)C>CO>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:14]=2[F:13])[N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: NCc1ccc(F)cc1F
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NCc2ccc(F)cc2F)nc(Cl)n1
Reaction time: 1 h
Yield: 45.93 %

Procedure:
A suspension of methyl 2,6-dichloropyrimidine-4-carboxylate (1 g, 4.87 mmol) in methanol (20 ml) was cooled to −20° C., to this 2,4-difluoro benzylamine (0.627 mg, 4.39 mmol) and triethylamine (0.98 mg, 9.74 mmol) were added. The reaction mixture was stirred at same temperature for 1 hr then at room temperature for 4 hrs. Methanol was removed under vacuum. The residue was purified by column chromatography to get the title compound.