Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].O>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(S([O-])(=O)=O)=CC=2C(C)C)CCCCC1.[Na+].C(#N)C>[CH3:19][O:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(C#Cc2ccccc2)cc1
Yield: 85.5 %

Procedure:
The general procedure described in Example 27 was used with 4-chlorobenzoic acid (79 mg, 0.50 mmol), phenylacetylene (0.072 mL, 0.65 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.5 mL), 12 h, 100° C. The product was isolated as a white solid (101 mg, 86%). Mp=114° C. (lit. 113-115° C.). 1H NMR (400 MHz, CDCl3) δ: 8.04 (d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.57 (m, 2H), 7.39 (m, 3H). 13C NMR (125 MHz, CDCl3) δ: 166.6, 131.9, 131.6, 129.64, 129.56, 128.9, 128.6, 128.1, 122.8, 92.5, 88.8, 52.3.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[K].[CH3:21][NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH:23]1([N:22]([CH3:21])[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:1]3[C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[N:3]=[CH:2]3)=[CH:19][CH:18]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CNC1CCCCC1
Reactant: O=C(O)c1ccc(Cn2cnc3cnccc32)cc1
Agent: [K]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(Cn2cnc3cnccc32)cc1)C1CCCCC1
Temperature: -5 °C
Reaction time: 15 h

Procedure:
A stirred suspension of 4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl)benzoic acid, potassium salt (0.78 g, 0.0027 mol) in dry dimethylformamide (5 ml) was treated with N-methylcyclohexylamine (0.36 g, 0.0032 mol) and triethylamine (0.54 g, 0.0054 mol). The reaction mixture was cooled to -5° C. and then treated with diphenylphosphoryl azide (0.81 g, 0.0030 mol). The resulting mixture was allowed to warm up to room temperature and stirred for an additional 15 hours. The solvent was evaporated off under reduced pressure to yield a crude product which was purified by column chromatography (silica gel, 5% ethanol in chloroform) and recrystallized from ethyl acetate to yield N-cyclohexyl-N-methyl-4-(1H-imidazo[4,5-c]pyridin-1-yl-methyl)benzamide as a colorless crystalline solid, having a melting point of 132°-134° C. and the following physical characteristics:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:16][CH:17]1[CH2:19][CH2:18]1)[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[C:23]([CH2:31]Br)[CH:22]=1.C(N(CC)C(C)C)(C)C.O1CCOCC1.[CH3:48][N:49]1[C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][CH:51]=[N:50]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[CH:17]1([CH2:16][C@H:3]([N:2]2[CH2:31][C:23]3[C:24](=[CH:29][CH:30]=[C:21]([C:53]4[N:49]([CH3:48])[N:50]=[CH:51][CH:52]=4)[CH:22]=3)[C:25]2=[O:27])[CH2:4][N:5]2[C:6](=[O:15])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]2=[O:14])[CH2:19][CH2:18]1
Reactant: N[C@@H](CC1CC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc2c(c1)CN([C@@H](CC1CC1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
A mixture of 2-[(2S)-2-amino-3-cyclopropylpropyl]-1H-isoindole-1,3(2H)-dione hydrochloride (257.75 mg, 0.91806 mmol), methyl 4-bromo-2-(bromomethyl)-benzoate (275.80 mg, 0.89555 mmol), N,N-diisopropylethylamine (0.50 mL, 2.9 mmol) and 1,4-dioxane (5.0 mL, 64 mmol) was stirred at 130° C. for 2 hours under microwave irradiation. After the reaction was completed, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (250.1 mg, 1.202 mmol), bis(tri-t-butylphosphine)palladium (51.1 mg, 0.100 mmol) and water were added. The reaction mixture was stirred at 110° C. for 40 mins under microwave irradiation. Direct purification on prep.HPLC afforded 56 mg (14.2% yield) of the desired final compound. LC-MS found: 441.1 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[N:14][C:13]=23)O1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.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>[CH3:39][O:38][C:34]1[N:33]=[C:32]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]4)=[N:14][C:13]=23)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(B4OC(C)(C)C(C)(C)O4)c3n2)CC1
Reactant: COc1cccc(Br)n1
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: CCOC(C)=O
Solvent: O
Product: COc1cccc(-c2cnn3ccc(N4CCN(C(=O)OC(C)C)CC4)nc23)n1
Yield: 67.5 %

Procedure:
To 65 mg (0.157 mmol) of isopropyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate in a microwave vial was added, 29 mg (0.157 mmol) of 2-bromo-6-methoxypyridine, 43 mg (0.313 mmol) of K2CO3, 18 mg (0.016 mmol) Pd(PPh3)4, 3 mL of DME and then 1 mL water. The resulting mixture was microwaved at 125° C. for 0.33 hr. It was diluted with EtOAc, washed with brine, and the organic layer dried over MgSO4. It was concentrated and purified on the neutral PREP HPLC to obtain 42 mg of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J=6.32 Hz, 6 H) 3.60-3.74 (m, 4 H) 3.81 (br. s., 4 H) 4.04 (s, 3 H) 5.00 (quin, J=6.25 Hz, 1 H) 6.39 (d, J=7.83 Hz, 1 H) 6.55 (dd, J=8.08, 0.76 Hz, 1 H) 7.62 (dd, J=8.08, 7.58 Hz, 1 H) 7.83-7.93 (m, 1 H) 8.37 (d, J=7.83 Hz, 1 H) 8.66 (s, 1 H). LRMS (ESI) m/e 397 [(M+H)+, calcd for C20H24N6O3 396 ].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[CH3:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH:16]=2)[C:11]([NH:32][CH2:31][C:28]2[CH:29]=[N:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)nc1
Reactant: Cc1ccc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCCC3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged 3-(5-methylpyridin-2-yl)-5-(pyrrolidine-1-carbonyl)benzoic acid (80 mg, 0.26 mmol), (6-methylpyridin-3-yl)methanamine (60 mg, 0.49 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (90 mg, 0.47 mmol), 1-hydroxybenzotriazole hydrate (80 mg, 0.52 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and methylene chloride (5 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified via preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27].C(OCC)C.CCCC(C)C>C(#N)C>[Br-:24].[CH3:35][C:32]1[N:33]=[CH:34][C:29]([NH:28][C:26]([CH2:25][N+:1]23[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:27])=[N:30][CH:31]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccs2)CCCCCC1
Reactant: Cc1cnc(NC(=O)CBr)cn1
Solvent: CC#N
Solvent: CCCC(C)C
Solvent: CCOCC
Product: Cc1cnc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4cccs4)CCCCCC2)C3)cn1
Product: [Br-]
Yield: 32.2 %

Procedure:
1-Thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 5d) (48 mg) was dissolved in acetonitrile (2 mL) and 2-bromo-N-(5-methyl-pyrazin-2-yl)-acetamide (Example 9a) (33 mg) was added. After stirring for 1 week diethyl ether (8 mL) and isohexane (5 mL) were added. The crystals were collected by filtration, washed with ethyl acetate (2×4 mL) and dried to afford the titled compound (26 mg).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[OH:28][C:29]1[CH:30]=[C:31]([C:35]#[CH:36])[CH:32]=[CH:33][CH:34]=1>>[OH:28][C:29]1[CH:30]=[C:31]([C:35]#[C:36][C:13]2[CH:14]=[C:15]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]4[N:19]=[CH:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)[O:10]3)=[CH:11][CH:12]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: C#Cc1cccc(O)c1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3cccc(O)c3)ccc12

Procedure:
7-(3-hydroxyphenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 28% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 3-hydroxyphenylacetylene. The title compound was isolated as a yellow solid and as a 80/20 mixture of Z/E oxime isomers.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)O.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25]>C(O)(C)C.Cl>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=[N:22][NH:23][C:24](=[NH:25])[NH2:26])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2ccccc12
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CC(C)O
Product: N=C(N)NN=Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 80 °C
Yield: 20 %

Procedure:
A mixture of DMF (11.0 mL, 142 mmol) and phosphorous oxychloride (3.63 mL, 39 mmol) is stirred at 0° C. for 1 h, a 0.2 mL portion is pipetted into a solution of 2-phenylindole (96 mg, 0.5 mmol) in DMF at 5° C. This reaction mixture is stirred at 5°-10° C. for 1 h, quenched with water, stored at −200 for 16 h and filtered. The filtercake is washed with water and dried in vacuo to afford the 2-phenylindole-3-carboxaldehyde intermediate. A suspension of the thus-obtained 2-phenylindole-3-carboxaldehyde (44.2 mg, 0.2 mmol) in isopropanol and concentrated HCl (50 μL) is treated with aminoguanidine bicarbonate (27 mg, 0.2 mmol), heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product, 28 mg (20% yield), identified by mass spectral and HPLC analyses (M+H) 277; retention time 3.76 min.
Reaction SMILES: [BH4-].[Na+].C([C:7]1[S:11][C:10](C=S)=[CH:9][CH:8]=1)CCC.[CH3:14][OH:15]>[OH-].[Na+].C1COCC1>[OH:15][CH2:14][C:10]1[S:11][C:7]([S:11][CH2:10][CH2:9][CH2:8][CH3:7])=[CH:8][CH:9]=1
Reactant: CO
Reactant: CCCCc1ccc(C=S)s1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCSc1ccc(CO)s1
Reaction time: 2 h

Procedure:
A solution of NaBH4 (5.3 g, 0.141 mol) in methanol (29.0 g) and sodium hydroxide (20%, 56.0 mL) was added dropwise to a solution of 45 (56.47 g, 0.282 mol) in THF (75 mL) at room temperature. The mixture was stirred for 2 hours, extracted with ethyl ether 3×150 mL), the combined extracts washed with brine and dried (MgSO4). After solvent removal, the crude product 46 was obtained as an oil (55.4 g, 97%); 1H NMR δ: 0.88 (t, 3 H, J=7.3 Hz, CH3), 1.39 (m, 2 H, CH3—CH2), 1.57 (m, 2 H, CH3—CH2—CH2),1.88 (s, 1 H OH), 2.76 (t, 2 H, J=7.3 Hz, CH2—S), 4.73 (s, 2 H, CH2—OH), 6.83 (d, 1 H, J=3.5 Hz, aromatic H), 6.94 (d, 1 H, J=3.5 Hz, aromatic H); λmax/nm (εmax/dm3 mol−1cm−1) 275.5 (3600); LRMS(EI+) calc. for C9H14OS2: 202.1, found 202.1. The product was used without further purification in the preparation of 47.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([OH:12])=O)[C:6]=1[CH3:7].[CH3:44][N:45]([CH3:57])[C:46]1[NH:52][CH2:51][C:50]2[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=2[CH2:48][N:47]=1.C(N(C(C)C)C(C)C)C>ClCCCl.C1COCC1.CN(C1C=CN=CC=1)C>[CH2:35]([N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:52]2[CH2:51][C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[CH2:48][N:47]=[C:46]2[N:45]([CH3:57])[CH3:44])=[O:12])[N:4]=1)=[O:43])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Reactant: CN(C)C1=NCc2ccccc2CN1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3CN=C2N(C)C)c(C)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.8 %

Procedure:
To a solution of 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 36 mg, 0.058 mmol) in DCE (1.0 mL) was added 1-chloro-N,N-2-trimethylprop-1-en-1-amine (15 μL, 0.12 mmol). The resulting reaction mixture was stirred at room temperature for 1.5 h. A solution of N,N-dimethyl-2,5-dihydro-1H-benzo[e][1,3]diazepin-3-amine (Rodriguez, H. R. et al., J. Org. Chem., 33:670-676 (1968)) (11 mg, 0.058 mmol) in THF (1.0 mL) was then added, followed by DMAP (7 mg, 0.058 mmol) and i-Pr2EtN (50 μL, 0.29 mmol). The resulting reaction mixture was stirred at room temperature for 12 h, then concentrated in vacuo and purified by preparative HPLC to give the title compound (11 mg, 24%). 1H NMR (DMSO-d6, mixture of amide rotamers) δ 10.31 (br s, 1H), 8.56 (br s, 1H), 8.32-7.87 (m, 7H), 7.77-7.57 (m, 2.5H), 7.33-7.05 (m, 3H), 6.98 (br s, 0.5H), 5.09-4.53 (m, 3H), 4.08 (br s, 2H), 3.86-2.85 (m, 9H), 2.14 (s, 3H), 1.71-1.41 (m, 3H), 1.36-1.07 (m, 3H), 0.99-0.80 (m, 4.5H), 0.54 (br s, 3.5H); MS(ESI+) m/z 796.8 (M+H)+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6].[F:8][C:9]1[C:10](I)=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]>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.CN(C=O)C.CCN(CC)CC>[F:8][C:9]1[C:10]([C:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]
Reactant: C#CCNC(N)=O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNC(N)=O)c21

Procedure:
Using Method C above, 2-propynylurea (50 mg, 0.51 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[5-fluoro-2,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]urea. (Yield 11 mg, 16%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[N:9][OH:10])=[N:6][CH:5]=[N:4]1)[CH3:2].[CH2:11]([OH:13])[CH3:12]>[OH-].[OH-].[Pd+2]>[C:11]([O-:10])(=[O:13])[CH3:12].[CH2:1]([N:3]1[C:7]([CH2:8][NH3+:9])=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCO
Reactant: CCn1ncnc1C=NO
Agent: [Pd+2]
Agent: [OH-]
Product: CC(=O)[O-]
Product: CCn1ncnc1C[NH3+]
Reaction time: 14 h

Procedure:
A mixture of 1-ethyl-1H-1,2,4-triazole-5-carbaldehyde oxime (6.17 g, 44 mmol), 10% palladium hydroxide on carbon (2.9 g) acetic acid (125 mL) and ethanol (125 mL) were stirred under an atmosphere of hydrogen for 14 hours. The reaction mixture was filtered and concentrated in vacuo to give the title compound (7.7 g) 1H-NMR (d6-DMSO) δ 1.32 (3H, t, J=7 Hz), 1.89 (3H, s), 3.89 (2H, br), 4.17 (2H, q, J=7 Hz), 7.80 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]2[CH2:24][CH:23]([C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)[CH2:22]2)[CH:15]=1>CC(N(C)C)=O>[CH3:30][N:29]1[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N:26]=[C:25]1[CH:23]1[CH2:24][N:21]([C:16]2[CH:15]=[C:14]([N:4]3[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]3)[N:19]=[C:18]([CH3:20])[N:17]=2)[CH2:22]1
Reactant: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Reactant: Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cnn(-c2cc(N3CC(c4nc5ccccc5n4C)C3)nc(C)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-methylpyrazole (10.5 mg, 0.13 mmol) in DMA (0.65 mL) in a microwave vial was added Cs2CO3 (83 mg, 0.26 mmol) and the mixture was stirred at rt. After 15 min, Intermediate 3 (40 mg, 0.13 mmol) was added and the tube was capped, sealed, and heated at 150° C. for 3 h. The reaction was cooled to rt, filtered through a syringe filter and purified by reverse-phase preparative chromatography (5-50% acetonitrile/water+0.1% TFA) to give Example 2. 1H NMR: (500 MHz, CD3OD) δ 8.31 (m, 1H), 7.76 (m, 1H), 7.54 (m, 1H), 7.33 (m, 3H), 6.62 (s, 1H), 4.64 (m, 4H), 4.31 (m, 1H), 3.73 (s, 3H), 2.51 (s, 3H), 2.14 (s, 3H) ppm. MS: m/z=360.5 (M+H).
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]([N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:16]([C:18]([OH:20])=O)[CH3:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)=O.C(Cl)(Cl)(Cl)Cl.CC(C)(C)C(Cl)=O.C[Mg]Cl>O1CCCC1>[CH3:1][C:18]([CH:16]([N:15]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:17])=[O:20]
Reactant: C[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: C[Mg]Cl
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)C(C)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.75 h
Yield: 65 %

Procedure:
Triethylamine (8.85 mmol, 1.24 mL) was added under an argon atmosphere to a stirred solution of N,N-dibenzylalanine (8.85 mmol, 2.38 g) in tetrahydrofuran (THF) (53.0 mL) at -30° C. (dry ice/CCl4 bath). Trimethyl acetyl chloride (8.85 mmol, 1.42 mL) was then added dropwise via syringe and the turbid solution was allowed to stir at -30° C. for 30 minutes before dropwise addition of a solution of methylmagnesium chloride in THF (3.0M, 1.07 eq., 9.5 mmol, 3.23 mL) over 10 minutes. The solution was stirred for 45 minutes and then quenched with saturated solution of NH4Cl (5.0 mL). The solution was extracted with Et2O, the organic extracts washed with brine, dried over MgSO4, and filtered. The solvent was evaporated in vacuo and the residue was subjected to flash column chromatography on silica gel with 8:1 hexanes/ethyl acetate to isolate a pure product in 65% yield. Colorless oil; R=0.43 (7:1 hexanes/ethyl acetate) 1H NMR (300.15 MHz) δ 1.19 (d, J=5.4 Hz, 3 H), 2.25 (5, 3 H), 3.39 (q, J=6.9 Hz, 1 H), 2.57 (AB quartet, δA =3. 33, δB =3. JAS=13.8 Hz, 4 H), 7.19-7.43 (m, 10 H); 13C NMR (75.5 MHz 7.1, 27.7, 54.6, 62.9, 27.2, 128.5, 128.8, 139.3, 210.8; IR (Neat) 1710 cm-1 ; MS (low resolution) m/e 268 M+H 22%), 224 (MeCHNBn2, 100%); HRMS for C18H22NO: 268-1709 (calc'd 268-1676); Anal: calc'd for C18H21NO: C 80.68, H 7.92, N 5.24; Found: C 80.79, H 7.95, N 5.17.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([SH:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.Cl[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[O:16])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: O=C(CCl)Nc1cccc(C(F)(F)F)c1
Reactant: CSc1nc(N)nc(S)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc(N)nc(SCC(=O)Nc2cccc(C(F)(F)F)c2)c1C#N
Yield: 78 %

Procedure:
To a 50 mL round-bottomed flask were added 2-Amino-4-mercapto-6-methylsulfanyl-pyrimidine-5-carbonitrile (3, 153 mg, 0.77 mmol, 1.0 eq.), 2-Chloro-N-(3-trifluoromethyl-phenyl)-acetamide (4, 184 mg, 0.77 mmol), potassium carbonate (106 mg, 0.77 mmol) and acetone (10 mL). The reaction mixture was heated to reflux for 10 min. After removal of potassium carbonate by filtration, the reaction mixture was concentrated to solid. Recrystallization with ether-ethyl acetate gave white solid (240 mg, 80%). LC-MS: (ES+) m/z 400.0 (M+1). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.50 (s, 1H), 8.04(s, 1H), 7.73 (d, 1H), 7.54 (t, 1H), 7.39 (d, 1H), 4.07 (s, 2H), 2.44 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][C:12]=1[Cl:22].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[Cl:22]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 4-[N′-(2-bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 3.37 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 4-[N′-(2-bromophenyl)ureido]-3-chlorophenylacetic acid (1.03 g, 80%) as colorless powder. 1H-NMR (DMSO-d6) δ 3.56 (s, 2H), 7.00 (m, 1H), 7.17 (dd, J=9.0, 1.7 Hz, 1H), 7.32–7.40 (m, 2H), 7.62 (dd, J=8.0, 1.2 Hz, 1H), 7.95 (m, 2H), 8.83 (s, 1), 9.01 (s, H), 12.41 (br, 1H); MS(FAB) m/z 385 (M++2), 386(M++4), 388 (M++6).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][C:6]=1[CH3:14].[NH3:15]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([S:10]([NH2:15])(=[O:12])=[O:11])=[CH:7][C:6]=1[CH3:14]
Reactant: COCCc1sc(S(=O)(=O)Cl)cc1C
Reactant: N
Solvent: CC(C)=O
Product: COCCc1sc(S(N)(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.40 g (55 mM) 5-(2-methoxy-ethyl)-4-methyl-thiophene-2-sulfonyl chloride in 20 ml acetone was added 5 ml of an aqueous solution of ammonia (25%) and the mixture was stirred at room temperature for 1 h. The mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was dried over sodium sulfate and evaporated. The residue purified by chromatography on silica gel crystallized form cyclohexane/diethyl ether to yield 0.89 g of the title compound as light red solid. MS (ISN) M−H+=233.8