Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCn1ccnc(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1ccnc(-c2ccc(Cl)cc2)c1=O
Yield: 47.6 %

Procedure:
To 200 mg (0.98 mM) of 3-bromo-1-ethylpyrazin-2(1H)-one and 57 mg (0.05 mM) of palladium tetrakis triphenylphosphine in 4 ml of toluene were added, under nitrogen, 231.0 mg (1.48 mM) of 4-chlorophenylboronic acid and 2.9 ml of 2M sodium carbonate aqueous solution The mixture was stirred for 3 h at reflux under nitrogen atmosphere, and then at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, over anhydrous sodium sulfate, and concentrated. The compound was purified through a silica plug, eluting with dichloromethane, which afforded 110 mg of 3-(4-chlorophenyl)-1-ethylpyrazin-2(1H)-one as a solid.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([CH:7]=[CH:8][C:9]2[N:19]=[C:12]3[N:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[N:4]([CH3:20])[N:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C1([O-])C=CC=CC=1.[Na+]>O1CCOCC1>[N:21]1([C:2]2[N:6]=[C:5]([CH:7]=[CH:8][C:9]3[N:19]=[C:12]4[N:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[N:11]4[N:10]=3)[N:4]([CH3:20])[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C)n2nc(C=Cc3nc(Br)nn3C)nc2n1
Reactant: C1CNC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C)n2nc(C=Cc3nc(N4CCC4)nn3C)nc2n1
Yield: 27.3 %

Procedure:
A solution of 2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (59 mg, 177 μmol, Eq: 1.00) in dioxane (2.11 ml) was purged with argon, then azetidine (15.1 mg, 17.8 μl, 265 μmol, Eq: 1.5), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.17 mg, 14.1 μmol, Eq: 0.08), tris(dibenzylideneacetone)dipalladium chloroform complex (7.31 mg, 7.06 μmol, Eq: 0.04) and sodium phenolate (20.5 mg, 177 μmol, Eq: 1.00) were added. The vial was capped and irradiated at 140° C. for 60 minutes in the microwave oven. Chromatography afforded 2-[2-(5-azetidin-1-yl-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (15 mg/27.4%) as a light yellow solid. MS: m/z=311.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([C@@H:29]2[CH2:33][O:32][C:31](=[O:34])[NH:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:30]1[C@H:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:33][O:32][C:31]1=[O:34])=[O:4]
Reactant: O=C1N[C@H](C2CCCCC2)CO1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)OC[C@H]1C1CCCCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A heavy wall flask was charged with trans-cyclohexane diamine (18.9 mg, 0.17 mmol, 0.5 equiv), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (100 mg, 0.332 mmol, 1.0 equiv), K2CO3 (92 mg, 0.664 mmol, 2.0 equiv), CuI (31.6 mg, 0.166 mmol, 0.5 equiv), (R)-4-cyclohexyl-oxazolidin-2-one (56.2 mg, 0.332 mmol, 1.0 equiv) and 1,4-dioxane (0.5 mL). The mixture was flushed with N2 and stirred at 110° C. for 18 hours, after which the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel, EtOAc/heptane 30% to give product 54 mg (yield 42%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH2:32]([O:34][C:35]([C:37]1([NH2:40])[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:40][C:37]3([C:35]([O:34][CH2:32][CH3:33])=[O:36])[CH2:39][CH2:38]3)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: CCOC(=O)C1(N)CC1
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Product: CCOC(=O)C1(NC(=O)c2cccc(-c3noc(-c4ccc(-c5ccccc5C)c(COC)c4)n3)c2)CC1

Procedure:
The title compound was prepared following procedure described in Example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 130, and 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride. The title compound was obtained as a white foam (120 mg, 98%). 1H NMR: (DMSO-d6, 300 MHz) δ 9.35 (m, 1H), 8.60 (m, 1H), 8.35 (m, 1H), 8.29 (m, 1H), 8.19 (m, 1H), 8.09 (m, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.39-7.26 (m, 3H), 7.15 (m, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.25 (s, 3H), 2.04 (s, 3H), 1.47 (m, 2H), 1.21 (m, 1H), 1.15 (t, J=7.1 Hz, 3H). LC/MS (Method B): 512.2 (M+H)+ 510.3 (M−H)−. HPLC (Method A) Rt: 5.27 min (purity: 99%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]1[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[C:33]([CH:36]=1)[CH:34]=O.C[O-].[Li+]>CN(C=O)C.CO>[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]1[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[C:33](/[CH:34]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:8][CH:9]=2)=[O:3])[CH:36]=1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)Nc3ccccn3)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
Ex-57A: A solution of 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 451 mg, 1.63 mmol) and 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 459 mg, 1.63 mmol) in DMF (10.0 mL) and MeOH (5.0 mL) was treated with lithium methoxide (248 mg, 6.52 mmol). The reaction mixture was stirred at room temperature for 3 h under nitrogen, quenched with water (50 mL), and extracted with (3:1) ethyl acetate/THF (4×30 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (2–5% MeOH in dichloromethane) to give 735 mg (65%) of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-yl-benzenesulfonamide as a yellow oil. 1H-NMR (300 MHz, DMSO-d6) 8.21 (d, 2H, J=7.5), 8.18 (s, 1H), 8.00 (m, 4H), 7.81 (d, 1H, J=15.0 Hz), 7.74 (t, 2H, J=7.5 Hz), 7.17 (m, 2H), 7.05 (t, 2H, J=7.2 Hz), 6.80 (m, 3H), 6.52 (t, 1H), J=7.5 Hz), 5.43 (d, 1H, J=6.9 Hz), 3.96 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][C:17]2[N:22]=[C:21]([N:23]([CH3:25])[CH3:24])[C:20]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][C:17]2[N:22]=[C:21]([N:23]([CH3:24])[CH3:25])[C:20]([CH2:26][C:27]([OH:29])=[O:28])=[CH:19][N:18]=2)=[CH:31][CH:32]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1nc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.9 %

Procedure:
To a mixture of methyl [2-(4-{[(benzyloxy)carbonyl]amino}benzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (1.51 g, 3.48 mmol) in tetrahydrofuran (8 mL) and methanol (15 mL) was added 1N NaOH aq. (5 mL). The reaction mixture was stirred for 20 hours at room temperature and concentrated under reduced pressure. The residue was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. This residue was dissolved with chloroform/methanol (10:1) and the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residual solid was recrystallized with acetonitrile/ethanol (10:1) to give [2-(4-{[(benzyloxy)carbonyl]amino}benzyl)-4-(dimethylamino)pyrimidin-5-yl]acetic acid (1.14 g, 78%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28](B(O)O)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O.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>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:28]4[C:29]([O:31][CH3:32])=[N:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ncc(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c(OC)n1
Temperature: 125 °C

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (4.1, 48 mg, 0.11 mmol, synthesized by procedures similar to those that were used to make compound 1.5 described in SCHEME 1), 2,4-dimethoxypyrimidin-5-ylboronic acid (4.2, 24 mg, 0.13 mmol), PdCl2(PPh3)2 (38 mg, 0.05 mmol), K2CO3 (23 mg, 0.16 mmol) in 1 mL acetonitrile and 1 mL water was degassed using argon stream and heated in microwave reactor at 125° C. for 15 min. The mixture was filtered and directly subjected to reverse phase prep HPLC to isolate the title compound. MS found for C20H17ClN6O3S (M+H)+ 457.1, 459.1 (Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.IC.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cccc(CC#N)c1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cccc(C(C)C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3-methoxyphenyl)acetonitrile (1.0 g, 6.79 mmol) and iodomethane (0.42 mL, 6.79 mmol) in THF (10 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1M in THF; 6.8 mL, 6.8 mmol). The reaction was warmed to room temperature and stirred for 1 hour. The mixture was partitioned between H2O and EtOAc and acidified with 1N aqueous HCl, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13](=[O:14])[N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH:7]3[C:6]=2[N:15]=1.CCN(C(C)C)C(C)C.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH3:26]>C(Cl)Cl>[CH2:25]([O:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([N:11]2[CH2:10][CH2:9][N:8]3[C:13](=[O:14])[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[N:15][C:6]=4[CH:7]3[CH2:12]2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)[CH3:26]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2c(n1)C1CNCCN1C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN3C(=O)c4ccc(C)nc4C3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a suspension of 2-methyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (may be prepared as described in Intermediate 8; 70 mg) in DCM (5 mL) was added DIPEA (0.241 mL, 1.378 mmol). To this was added 4-(ethyloxy)benzenesulfonyl chloride (80 mg) and this was allowed to stir at room temperature for 30 minutes. The reaction mixture was partitioned between DCM and saturated sodium bicarbonate solution in a hydrophobic frit. The aqueous layer was re-extracted with DCM. The combined organic phases were evaporated to an orange oil. The residue was purified by chromatography (25S silica cartridge) eluting with 0-5% methanol in DCM over 12 column volumes. The clean fractions were combined and evaporated to give the title compound as a white foam (84 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([CH3:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:20][C:16]1[CH:15]=[C:14]([C:11]2([CH3:23])[CH:10]3[CH:12]2[CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]3=[O:24])[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(c2cccc([N+](=O)[O-])c2)C2CN(Cc3ccccc3)C(=O)C21
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2cccc(N)c2)C2CN(Cc3ccccc3)C(=O)C21
Yield: 95.4 %

Procedure:
To a solution of 3-benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Preparation 28, 2 g, 6.2 mmol) in absolute ethanol (170 ml) was added water (30 ml), calcium chloride (344 mg, 3.1 mmol) and iron powder (3.02 g, 53.8 mmol). The mixture was heated to reflux under nitrogen for 4 h, then cooled. The solution was filtered through silica (10 g) eluting with methanol, then concentrated in vacuo to give the title compound as a white solid (1.73 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc(-c3ccccc3)c2)c1
Yield: 96 %

Procedure:
Commercial 3-bromoiodobenzene in an amount of 11 g, 8.7 g of commercial 3-biphenylboronic acid and 130 ml of toluene were mixed together. To the resultant mixture, 0.9 g of tetrakis(triphenyl-phosphine)palladium and 75 ml of a 2 M aqueous solution of sodium carbonate were added, and the reaction system was purged with argon. After the reaction mixture was heated under the refluxing condition for 8 hours, the reaction mixture was cooled by leaving standing. The formed crystals were separated by filtration and subjected to extraction with toluene. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. The solvent was removed using an evaporator. The residue was purified in accordance with the silica gel column chromatography (the developing solvent: hexane), and 11.8 g of 3-bromo-m-terphenyl was obtained as a white solid substance (the yield: 96%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.[NH2:13][C:14](N)=[O:15].N>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:14]([NH2:13])=[O:15])[CH2:4][CH2:3]1
Reactant: NC1CCC(=O)c2ccccc21
Reactant: NC(N)=O
Agent: N
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
Similarly, 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine and excess urea are mixed and heated until ammonia evolution ceases. The solid product, 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea, is washed with water, collected by filtration and dried.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]3)=[C:8]([CH3:22])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]4)=[C:8]([CH3:22])[C:6]=3[N:7]=2)=[CH:38][N:39]=1
Reactant: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 10.1 %

Procedure:
1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone (60 mg) was reacted with 34 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A. The product was purified by reverse phase HPLC to yield 6.9 mg of 178. MS (Q1) 485.1 (M)+
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[CH:3]=1.C([O-])(O)=O.[Na+].[NH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C.O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:18][CH2:19][C:20]([OH:22])=[O:21])[CH:3]=1
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 4-bromo-2,5-dichloronitrobenzene (1.000 g, 3.691 mmol) in DMF (10.0 mL) at 65° C. was added dropwise a solution of NaHCO3 (0.316 g, 3.76 mmol) and glycine (0.280 g, 3.73 mmol, Aldrich, used as received) in water (3.8 mL). The resulting suspension was stirred at 65° C. for 65 h. The bright orange suspension was then cooled to r.t., filtered, washed with water (1.0 mL) and dried under vacuum to afford 0.284 g (98%, based on recovered starting material) of pure title compound as an orange powder; m.p. 264°-265° C. (decomposed); 1H NMR (DMSO-d6):3.451 (d, 2H, J=3.9 Hz), 7.199 (s, 1H), 8.130 (s, 1H), 8.793 (t, 1H, J=3.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(CCBr)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CC(=O)c1ccc(CCN2CCN(c3ccc(Cl)cc3)CC2)cc1
Yield: 64 %

Procedure:
By the reaction of 1-(4-chlorophenyl)-piperazine with 4'-(2-bromoethyl)-acetophenone analogously to Example (41a), there is obtained 4'-{2-[1-(4-chlorophenyl)-piperazin-4-yl]-ethyl}-acetophenone. Yield 64% of theory; m.p. 141°-143° C. (recrystallised from ethyl acetate).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:41])([F:40])[C:20]([C:26]1[CH:39]=[CH:38][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][C:32]2=[O:37])=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:29]4[CH:38]=[CH:39][C:26]([C:20]([OH:25])([C:19]([F:18])([F:40])[F:41])[C:21]([F:24])([F:22])[F:23])=[CH:27][CH:28]=4)[C:32](=[O:37])[CH2:33]3)=[O:14])=[CH:15][CH:16]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: O=C1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.337 mmol, 79 mg), 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-2-one (0.281 mmol, 100 mg) and triethylamine (0.842 mmol, 85 mg) in dichloromethane (10 ml) was added 1-propanephosphonic acid cyclic anhydride (0.421 mmol, 268 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (30 mL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with 5% methanol/95% dichloromethane) to afford the title compound (36 mg). MS (ESI) m/z 573.0 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:3]=1.[N:20]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[C:6]([C:7]([N:28]2[CH2:29][CH2:30][CH:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:26][CH2:27]2)=[O:9])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1nn(-c2cccc([N+](=O)[O-])c2)c(C)c1C(=O)O
Product: Cc1nn(-c2cccc([N+](=O)[O-])c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 93 %

Procedure:
In analogy to the procedure described in Example 18], 3,5-dimethyl-1-(3-nitro-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the tide compound in 93% yield as green foam. MS: 398.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])[N:11]([CH3:20])[N:10]=1.[Br:21]Br>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16]([Br:21])=[CH:17][C:18]=2[CH3:19])[N:11]([CH3:20])[N:10]=1
Reactant: BrBr
Reactant: Cc1ccsc1-c1nc(-c2c(F)cccc2Cl)nn1C
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)sc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 81.1 %

Procedure:
3-(2-fluoro-6-chlorophenyl)-5-(3-methyl-2-thienyl)-1-methyl-1,2,4-triazole (1.18 mmol., 364 mg) was dissolved in glacial acetic acid (4 ml). Bromine (2.36 mmol, 0.124 ml) was added in two portions and the reaction allowed to stir 5 days at room temperature. Diluted with water and extracted into diethyl ether, washed with saturated NaHCO3 and brine, dried over MgSO4. Concentrated to a white solid. Wgt. 0.51 g, recrystallized from hexane ethyl acetate to afford the product as a white solid (0.37 g, 81%) MP 117-118° C.; Anal. Calcd. For C14H10BrClFN3S; C, 43.44; H, 2.60; N, 10.86. Found; C, 43.46; H, 2.71; N, 10.81.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: O=C(O)c1csc(Cl)n1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(Cl)n2)c1

Procedure:
Carboxylic acid (79) (220 mg, 1.34 mmol) was coupled to aniline (60) (257 mg, 1.34 mmol) using Method C to give the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[C:2]=[O:3].[CH3:18][N:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[C:22]=2[CH:21]=[N:20]1.N1C2C=CC=C(N)C=2C=N1>>[N:11]1([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][NH:1][C:2]([NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:22]=3[CH:21]=[N:20][N:19]4[CH3:18])=[O:3])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(N2CCCCCC2)cc1
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCCC4)cc3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]azepane and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 8.97 (s, 1H), 8.18 (s, 1H), 7.65 (d, 1H), 7.14 (m, 4H), 7.11 (d, 1H), 6.95 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.27 (m, 4H), 1.90 (m, 4H), 1.53 (m, 4H); MS (ESI) (M+H)+378.