Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3]1.N#N.[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:1][C:2]1([Br:12])[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3]1
Reactant: BrC1Cc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: Clc1ccccc1
Product: BrC1(Br)Cc2ccccc21
Temperature: 120 °C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
Bromobenzocyclobutene (91.5 g, 0.5 mol) and chlorobenzene(anhydrous, 2500 mL) were charged into a four-neck 5 L flask equipped with mechanical stir, condenser, N2 (in and outlet) and thermometer. The reaction mixture was heated to 120° C., and N-bromosuccinimide (111.3 g, 0.625 mol) was gradually charged over 30 min., followed by slowly feeding a mixture of a free radical azo compound source (VAZO™ 68) (14.0 g, 0.05 mol) and chlorobenzene (500 mL) over 30 min. Then the reaction mixture was heated to 133° C. (mild reflux) and kept at that temperature for 6 hr. The mixture was then cooled to room temperature overnight, and chlorobenzene was removed by vacuum evaporation. The crude product was extracted with hexane. After removal of hexane, 1-bromo-bromobenzocyclobutene (1-Br-BrBCB) (80-85° C/0.35 torr, 90 g, ca. 93% purity) was obtained by vacuum distillation.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=C(O)C=2)C(F)=CN=1.[S:43]1[C:47]2C=CC=CC=2[C:45](CN)=[CH:44]1>>[S:43]1[C:44]2[CH:45]=[CH:21][CH:22]=[CH:23][C:24]=2[C:25]([CH2:20][NH:19][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)=[CH:47]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: NCc1csc2ccccc12
Agent: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(NCc3csc4ccccc34)ncc2F)c1
Yield: 53 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and benzothiophen-3-ylmethylamine (100 mg, 0.61 mmol) gave N2-(benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 53%). 1H NMR (CDCl3): δ 4.82 (d, J=6.0 Hz, 2H), 6.45 (dd, J=8.1 Hz, 1H), 6.70 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.03 (t, J=8.1 Hz, 1H), 7.22 (m, 1H), 7.34 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (m, 1H), 7.89-7.92 (m, 2H); 19F NMR (282 MHz, CDCl3): δ −170.02; LCMS: ret. time: 21.29 min.; purity: 92.97%; MS (m/e): 367.03 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)([OH:22])[CH2:19]1)=[O:17].Cl.[O:37]1CCO[CH2:39][CH2:38]1>CO>[C:38]([O:22][C:20]1([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:19][N:18]([C:16]([C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:17])[CH2:21]1)(=[O:37])[CH3:39]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: CO
Product: CC(=O)OC1([C@@H]2CCCCN2)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Yield: 62.5 %

Procedure:
1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (24 mg, 0.040 mmol) was dissolved in methanol (2 mL) and treated with 4 N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at reflux for 20 minutes. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate (14 mg, 0.025 mmol, 63% yield): 1H NMR (400 MHz, d6-DMSO): 8.62 (br s, 1H), 8.46 (s, 1H), 8.18 (dd, 1H), 7.65 (dd, 1H), 7.45 (d, 1H), 7.37 (t, 1H), 7.16-7.08 (m, 1H), 4.25 (dd, 1H), 4.04 (dd, 1H), 3.90 (t, 1H), 3.70 (d, 1H), 2.95 (br d, 1H), 2.52-2.42 (m, 2H), 1.78-1.68 (m, 1H), 1.57 (br t, 1H), 1.47 (br d, 1H), 1.35-1.13 (m, 2H), 1.10-0.96 (m, 1H); MS (EI) for C20H22FIN4O2: 497 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C.C1COCC1>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Oc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1cccnc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Add potassium tert-butoxide (2.69 g, 24 mmol) to a 0° C. solution of 3-hydroxy-pyridine (1.90 g, 20 mmol) in DMF (30 mL) and THF (30 mL) stirring under N2. Add 2-(trimethylsilyl)ethoxy-methyl chloride (3.72 mL, 21 mmol) dropwise and allow to warm slowly to RT overnight. Add water to quench, stir for 5 minutes and concentrate. Dissolve in 20% i-PrOH/CHCl3, wash with saturated NaHCO3 solution (2×) and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-50% EtOAc/hexanes to afford the title compound (3.14 g, 70%) as yellow liquid. MS(IS) 226 (M+1). TLC: Rf=0.43 (50% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[N:22]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:32][CH2:31]4)=[O:34])=[CH:36][CH:37]=3)=[CH:15][C:6]1=2
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: O=C1CNc2ncc(I)cc2N1Cc1c(Cl)cccc1Cl
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)C(=O)CN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 35 %

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (60 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a brown solid (35% yield). M.p.=199° C., LCMS: m/z=564.03 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.89 (6H, m), 2.25 (1H, m), 2.59 (5H, s), 2.99 (3H, m), 3.80 (1H, bs), 4.26 (2H, d, J=1.3 Hz), 4.60 (1H, bs), 4.84 (1H, bs), 5.56 (2H, s), 7.17 (1H, m), 7.33 (5H, m), 7.41 (2H, d, J=8.1 Hz), 7.94 (1H, d, J=1.8 Hz),
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([C:15]2[NH:19][N:18]=[C:17]([NH2:20])[CH:16]=2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:20][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:14][CH2:13]3)[NH:19][N:18]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (5 g) and 5-cyclopropyl-1H-pyrazol-3-amine (5 g) in acetonitrile (40 mL) with diisopropylethylamine (6 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 5 g desired product. MS (electrospray): 280 (M+1) for C11H10ClN5O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.5 (d, 1H) 6.9 (d, 1H) 6.5 (s, 1H) 1.9 (m, 1H) 1.0 (m, 2H) 0.70 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20]([C:22]1[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1)=[O:21])(C)(C)C.CCN(CC)CC.[CH2:37]1[C:40]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][N:38]1C(OC(C)(C)C)=O>CS(C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:21])[C:22]1[CH:27]=[CH:26][C:25]([N:43]2[CH2:44][CH2:45][C:40]3([CH2:37][NH:38][CH2:39]3)[CH2:41][CH2:42]2)=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N2CCC3(CC2)CNC3)nc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
tert-Butyl[2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate F (20 mg, 0.088 mmol) was dissolved in 1 mL of DMSO and treated with Et3N(0.010 mL) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (20 mg, 0.047 mmol). The mixture was stirred at 90° C. for 18 h, partitioned between EtOAc and saturated NaHCO3, dried (MgSO4), filtered and concentrated), concentrated and the residue was purified by chromatography on SiO2 (EtOAc/CH2Cl2, 0% to 100%). The residue was dissolved in 1 mL of 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. Neutralization with EtOAc/sat'd NaHCO3 extraction and drying (MgSO4) gave desired product, N-[2-amino-5-(2-thienyl)phenyl]-6-(2,7-diazaspiro[3.5]non-7-yl)nicotinamide, which was confirmed by MS (ESI+): cal'd [M+H]+ 420.2, obs'd 420.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][O:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>CS(C)=O.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([S:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([N:37]5[CH2:38][CH2:39][CH:34]([O:33][CH3:32])[CH2:35][CH2:36]5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[CH:21][CH:22]=[N:23]2)=[N:28][CH:27]=1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: COC1CCNCC1
Solvent: CS(C)=O
Solvent: CO
Product: COc1cnc2c(Sc3ccc(Nc4nnc(N5CCC(OC)CC5)c5ccccc45)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 15 ml sealed pressure tube was charged with 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (120 mg, 0.269 mmol) and 4-methoxypiperidine (620 mg, 5.382 mmol), in 0.3 ml of DMSO. The sealed tube was placed in a preheated oil bath at 100° C. where it was stirred for 16 hours. The reaction was cooled to ambient temperature, diluted with 2 ml of MeOH, and the solution purified using Gilson Reverse Phase HPLC. The fractions containing the desired product was neutralized with saturated sodium bicarbonate and extracted with 10 ml of DCM (3×). The organics were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to afford N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(4-methoxypiperidin-1-yl)phthalazin-1-amine as a yellow solid. MS [M+H]+=525.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[CH3:10][N:11]([CH3:42])[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C@H:22]([C:27]([NH:29][C:30](=O)[C@H:31](CCC2C=CC=CC=2)[NH2:32])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[C:43]([C:46]#N)([CH3:45])=O.O>CN(C=O)C>[C:31]([C@@H:30]([NH:29][C:27](=[O:28])[C@@H:22]([NH:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH3:10])[CH3:42])=[CH:17][CH:16]=1)(=[O:20])=[O:19])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:45][CH2:43][C:46]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)#[N:32]
Reactant: CC(=O)C#N
Reactant: CC(C)C[C@H](NS(=O)(=O)c1ccc(N(C)C)cc1)C(=O)NC(=O)[C@@H](N)CCc1ccccc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(N(C)C)cc1)C(=O)N[C@H](C#N)CCc1ccccc1
Yield: 57 %

Procedure:
Cyanuric chloride (33 mg, 0.18 mmol) was added to a solution of N-[N-((4-dimethylaminophenyl)sulfonyl)-L-leucinyl]-L-homophenylalaninamide (80 mg, 0.18 mmol) in DMF (2 mL) at 0° C. After stirring for 2h, the reaction was quenched by addition of satd. NaHCO3, filtered, diluted with EtOAc, washed sequentially with H2O (×5), brine, dried over Na2SO4, and concentrated giving a yellow foam. The crude residue was fractionated by preparative HPLC (65% AcCN/H2O/0.1% TFA) giving the title compound (47 mg, 57%) as a white solid, m.p. 46-48° C. 1H NMR (400 MHz, CDCl3): δ: 7.74(2H, d, J=9), 7.37-7.34 (2H, m), 7.30-7.26 (2H, m), 7.23-7.21 (3H, m), 6.79 (1H, d, J=8.5), 4.91 (1H, bs), 4.70 (1H, ddd, J=8, 8, 8), 3.68-3.73 (1H, m), 3.06 (3H, s), 2.84-2.76 (2H, m), 2.16-2.09(2H, m), 1.63-1.56 (2H, m), 1.42-1.37 (1H, m), 0.88 (3H, d, J=6), 0.71 (3H, d, J=6).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[Cl:37][C:38]1[C:39]([C:48]([F:51])([F:50])[F:49])=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([C:48]([F:50])([F:49])[F:51])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[CH2:36][CH2:35]2)=[O:46])[C:42]=1[CH3:43]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccccn2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Pyridyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 8.11 (d, 1H), 7.53 (t, 1H), 6.85 (d,1H), 6.65 (t, 1H), 5.37 (s, 2H), 3.59–3.50 (m, 8H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=388.1, found=388.0.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:26]4[CH:25]=[N:24][C:33]5[C:28]([CH:27]=4)=[CH:29][CH:30]=[CH:31][CH:32]=5)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cnc4ccccc4c3)sc2n1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (90 mg, 0.208 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 3-quinolinylboronic acid (72.1 mg, 0.417 mmol), bis(triphenylphosphine)palladium(II) chloride (14.63 mg, 0.021 mmol) and potassium carbonate (101 mg, 0.730 mmol) and the reaction mixture heated at 100° C. for 30 min using a microwave reactor. The mixture was then filtered through celite, washing with DCM (30 mL×2) and the filtrate dried (phase separation cartridge) and concentrated. This residue was then purified by MDAP (basic conditions) and then further triturated with MeOH (2 mL) and dried, to afford the title compound (31.61 mg). LCMS (A) m/z: 480 [M+1]+, Rt 1.23 min (acidic).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[C:8]([O:20][CH3:21])[CH:7]=1)[CH3:2].[CH3:23][N:24](C)C=O>O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:23]#[N:24])=[C:8]([O:20][CH3:21])[CH:7]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Temperature: 80 °C

Procedure:
Ethyl(3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate (16.6 g) was dissolved in anhydrous dimethylformamide (100 mL). Zinc cyanide (3.4 g, 29 mmol) was added, and the solution was purged thoroughly with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (5.6 g, 4.9 mmol) was then added and the reaction mixture was heated to 80° C. for 4 h. After allowing the reaction mixture to cool to ambient temperature and diluting with water (200 mL), ethyl acetate (400 mL) was added and the mixture was filtered to remove any solids. The filtrate was transferred to a separatory funnel, and the layers separated. The aqueous layer was re-extracted with ethyl acetate (2×100 mL). The organic layers were combined and dried over magnesium sulfate. The dry organics were then filtered and evaporated to dryness under reduced pressure and excess dimethylformamide was removed by evaporation in vacuo at 65° C. for 1.5 h to yield crude product. The crude product was purified through silica gel chromatography (ethyl acetate/hexanes, 2:3) to yield ethyl(4-cyano-3-methoxyphenyl)acetate. 1H NMR (500 MHz, DMSO-d6), δ 7.67 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.0 (d, J=8.0 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.78 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); LC/MS (M+1)+=220.17; tR=1.36 min.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].C([Li])CCC.C(C([O:19][N+:20]([O-])=[O:21])=O)(F)(F)F>O1CCCC1.[N+]([O-])([O-])=O.[K+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N+:20]([O-:21])=[O:19])=[O:2]
Reactant: O=Cn1ccnc1
Reactant: O=C(O[N+](=O)[O-])C(F)(F)F
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: O=Cn1ccnc1[N+](=O)[O-]
Reaction time: 0.03 h
Yield: 62 %

Procedure:
1-formyl-imidazole (about 0.100 grams) was dissolved in 1 mL of tetrahydrofuran at room temperature. Immediately, 1 equivalent (eq.) of n-butyl lithium in about 1.6 M (molar) hexanes was added to the reaction mixture, followed by 1.2 eq. of freshly prepared 1:1 molar mixture of potassium nitrate (KNO3) and trifluoroacetic anhydride (TFAA) in tetrahydrofuran as solvent at about 0° C. to about 4° C. The active nitrating species (CF3C(O)ONO2), thus, was generated in situ and the reaction mixture was stirred further for about 1.5 minutes. The 1-formyl-2-nitro-1H-imidazole product was isolated and purified by flash column chromatography to yield the pure product (i.e., about 95% purity) in about 62% yield. The structure of the 1-formyl-2-nitro-1H-imidazole product was confirmed by 1H NMR spectroscopy. 1H NMR (CDCl3): δ 2.8 (s, 3H), 7.20 (d, 1H), 7.74 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:22])C(=O)OC(C)(C)C)=[C:11](I)[N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:23]([Cu])#[N:24]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:14][CH3:22])=[C:11]([C:23]#[N:24])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: CN(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1sc(-c2cncc(F)c2)nc1C#N
Temperature: 120 °C

Procedure:
To a nitrogen-purged solution of tert-butyl 2-(5-fluoropyridin-3-yl)-4-iodothiazol-5-yl(methyl)carbamate (1.0 g, 2.298 mmol) in DMF (8 mL) was added CuCN (288 mg, 3.22 mmol) and the mixture was heated in a microwave at 120° C. for 80 min. The mixture was diluted with ethyl acetate (75 mL) and successively washed with an aqueous solution (15 mL) of ethylene diamine (5% v/v), and brine, dried over MgSO4 filtered, and concentrated on a rotary evaporator under vacuum to give a yellow solid, 2-(5-fluoropyridin-3-yl)-5-(methylamino)thiazole-4-carbonitrile. The solid was used in the preparation of N-(4-cyano-2-(5-fluoropyridin-3-yl)thiazol-5-yl)-N-methyl-3-(methylthio)propanamide. To a solution of crude 2-(5-fluoropyridin-3-yl)-5-(methylamino)thiazole-4-carbonitrile (200 mg, 0.83 mmol) in CH2Cl2 (2 mL) were added K2CO3 (178 mg, 1.28 mmol) and 3-(methylthio)propanoyl chloride (130 mg, 0.94 mmol) followed by dimethylaminopyridine (21 mg, 0.17 mmol). The mixture was stirred at room temperature for 36 h and diluted with ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (5 mL). The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown gummy residue. This residue was purified by silica gel chromatography (6:4 hexane/ethyl acetate) to give N-(4-cyano-2-(5-fluoropyridin-3-yl)thiazol-5-yl)-N-methyl-3-(methylthio)propanamide as a pale yellow solid (164 mg, 57% yield): mp 97-98° C.; 1H NMR (300 MHz, CDCl3) δ 8.98 (bs, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.27 (dt, J=9.6, 1.8 Hz, 1H), 2.73 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.62, 2H), 2.09 (s, 3H), 2.03 (s, 3H): ESIMS m/z 337.2 (M+1).
Reaction SMILES: FF.[N+:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[C-:4].[H-].[Na+].[F:13][C:14]([F:25])([F:24])/[C:15](/Cl)=[N:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:15]([C:14]([F:13])([F:24])[F:25])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:4]1
Reactant: FC(F)(F)/C(Cl)=N/c1ccccn1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: FF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
The synthetic intermediate imine (Z)-2,2,2-trifluoro-N-(pyridin-2-yl)acetimidoyl chloride was prepared as described in Huang et al., J. Fluorine Chem., 74:279-282 (1995) and used without distillation. To ethyl isocyanoacetate (0.543 g, 4.8 mmol) in dry THF (50 mL) was added NaH (192 mg, 4 8 mmol, 60% dispersed in oil) at 0° C. and after 5 minutes, (Z)-2,2,2-trifluoro-N-(pyridin-2-yl)acetimidoyl chloride (1.0 g, 4.8 mmol) in 50 mL THF. The reaction mixture was allowed to warm to room temperature and then purified using an 80 g SiO2 column and a 50-100% EtOAc/hexanes gradient. The product eluted to yield 1.23 g (90% yield) of ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylate as a yellow oil. MS (M+1)=286.1; HPLC RT=1.08 minutes.
Reaction SMILES: C(C1C=CC(C2C=CC=CC=2F)=CC=1)#C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[CH:25][CH:24]=1.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:29]([C:26]1[CH:27]=[CH:28][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])=[CH:24][CH:25]=1)[CH3:30]
Reactant: CC(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: C#Cc1ccc(-c2ccccc2F)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccccc2Cl)cc1
Reaction time: 13 h
Yield: 64.5 %

Procedure:
The procedure of Example 1 was repeated, except that the 1-ethynyl-4-(2-fluorophenyl)benzene was replaced with 23.1 g of 4'-(2-chlorophenyl)acetophenone, the amount of benzene was increased to 150 ml, the amount of catalyst was increased to 3 g, the amount of sulfuric acid was increased to 2 ml, and the reduction was allowed to proceed for 13 hours. Evaporation of the benzene left a residue which was vacuum distilled to give 14 g of 1-ethyl-4-(2-chlorophenyl)benzene, bp 110°-112°/0.4 mm. The following elemental anaylsis was obtained:
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH:6]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[CH3:7])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH:6]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:11](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:9]1=[O:10])[CH3:7])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: CC(CN(C(C)C)C(C)C)N1C(=O)C(=O)c2ccccc21
Agent: Cl
Product: CC(CN(C(C)C)C(C)C)N1C(=O)/C(=N/NC(N)=O)c2ccccc21
Yield: 65.3 %

Procedure:
By using 1-(2-diisopropylamino-1-methylethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 10 was carried out and the reaction product was recrystallized from ethanol to obtain (E)-1-(2-diisopropylamino-1-methylethyl)isatin 3-semicarbazone having a melting point of 195°-197° C. (yield: 65.3%).