Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=[N:17][OH:18])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCC2(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(=NO)CCC2(C)C
Temperature: 70 °C

Procedure:
7-Methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (1.48 g, 7.24 mmol) (Winstein, S.; Heck, R. F, J. Org. Chem., 1972, 37, 825.) was dissolved in Ethanol (20 mL) then Hydroxylamine hydrochloride (0.61 g, 8.8 mmol) and Sodium acetate (1.20 g, 14.6 mmol) were added along with Water (20 mL). The mixture was warmed to 70° C. for 6 h, cooled and partitioned between 50 mL DCM, 10 mL satd. sodium bicarbonate and 40 mL water. The pH was 6-7. The phases were separated and the aq. extracted 2×50 mL DCM. The organic extracts were dried over sodium sulfate and concentrated in vacuo. 7-Methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime was isolated as a yellow solid (1.55 g, 98%) and used without purification. 1H-NMR (CDCl3): 7.42 (d, 1H, J=2.4 Hz), 7.27 (d, 1H, J=8.5 Hz), 7.23 (s, 1H), 6.91 (dd, 1H, J=2.4, 8.5 Hz), 3.81 (s, 3H), 2.85 (t, 2H, J=6.8 Hz), 1.73 (t, 2H, J=6.8 Hz), 1.27 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.OC(C(F)(F)F)=O.[CH3:21][S:22]([CH2:25][CH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1)(=[O:24])=[O:23].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:21][S:22]([CH2:25][CH2:26][C@H:27]1[CH2:28][CH2:29][C@H:30]([NH:33][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:31][CH2:32]1)(=[O:23])=[O:24]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CS(=O)(=O)CC[C@H]1CC[C@H](N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CS(=O)(=O)CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.10 g, 0.46 mmol), trans-4-[2-(methylsulfonyl)ethyl]cyclohexanamine TFA salt (0.12 g, 0.60 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) in isopropyl alcohol (1.0 mL) was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified on silica gel (eluting with 0 to 45% EtOAc in dichloromethane) to give the desired product. LCMS calculated for C16H22N3O4S2 (M+H)+: m/z=384.1. Found: 384.0.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[CH2:10]([C:14]1[S:23][C:22]2[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[NH:18][C:17](=S)[C:16]=2[N:15]=1)[CH2:11][CH2:12][CH3:13].[CH2:29]([C@H:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>ClCCl>[CH2:10]([C:14]1[S:23][C:22]2[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N:18]=[C:17]([N:41]3[CH2:40][CH2:39][NH:38][C@@H:37]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:42]3)[C:16]=2[N:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc2c(s1)Nc1ccccc1NC2=S
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
Add methyl trifluoromethanesulfonate (0.850 mL, 7.51 mmol) to a 0° C. solution of 2-Butyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (1.45 g, 5.01 mmol) in anhydrous dichloromethane. Rinse solids into reaction with dichloromethane and stir allowing reaction to slowly reach ambient temperature. After an overnight period, concentrate under reduced pressure to afford crude methylated intermediate. Take 1.06 g of this intermediates (2.0 mmol), and combine the intermediate and 2-(S)-Phenethyl-piperazine (0.38 g, 2.0 mmol), with anhydrous pyridine, heat to 100° C. and stir. After an overnight period, cool to ambient temperature and concentrate under reduced pressure to an oil (2.16 g), followed by two chromatographic purifications, eluting with a gradient of a 8% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane), gives the title compound (0.078 g). Mass spectrum (APCI+, m/e): 446 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 7.79 (s, 1H), 7.31–7.10 (m, 5H), 6.90–6.74 (m, 3H), 6.71–6.64 (m, 1H), 4.14–3.92 (br. m, 1H), 3.44–3.22 (m, 1H), 2.93–2.52 (m, 10H), 1.65–1.49 (m, 4H), 1.36–1.20 (m, 2H, J=7.1 Hz), 0.82 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].CN.[CH2:17]([N:19](CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:19][CH3:17])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NC

Procedure:
4-Methylamino-2-methylsulfanylpyrimidine-5-carboxylic acid ethyl ester was prepared from 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester and methylamine in tetrahydrofuran (THF) under basic conditions with triethylamine at temperatures between 5° C. and room temperature (RT).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[C:12](OS(C(F)(F)F)(=O)=O)=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([NH:39][C:12]2[C:9]3[CH2:10][CH2:11][N:5]([C:3](=[O:4])[C:2]([F:29])([F:28])[F:1])[CH2:6][CH2:7][C:8]=3[CH:15]=[CH:14][C:13]=2[C:16]([F:19])([F:17])[F:18])[CH3:38])=[CH:33][CH:32]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(N1CCc2ccc(C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: C[C@H](Nc1c(C(F)(F)F)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccc(F)cc1
Yield: 66.2 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (430 mg, 0.94 mmol) with (S)-1-(4-fluorophenyl)ethylamine (195 mg, 1.40 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to give (S)-6-[1-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (279 mg, 65%). MS (ES+) m/z: 449 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:32])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:27][CH2:28]1)(=[O:44])[CH3:43]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol) was suspended in methylene chloride (5 ml), and diisopropylethylamine (72 μl, 0.41 mmol) and acetyl chloride (29 μl, 0.41 mmol) were added. The mixture was stirred for half an hour at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. The solid was suspended in methanol and filtered off to give 7-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (117 mg, 71%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[F:58])#[N:51]>CN(C=O)C>[C:50]([C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[F:58])#[N:51]
Reactant: N#Cc1cc(-c2cccc(N)c2)ccc1F
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(F)c(C#N)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′-cyano-4′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 82% yield: LCMS (ESI) m/z 415 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:21]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:23]=5)[CH:17]=4)[N:12]([S:28]([C:31]4[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:11]=3)[N:7]=[C:6]([C:38](O)=[O:39])[CH:5]=2)[CH2:3][CH2:2]1.C[N:42](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[OH-]>CN(C=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:21]([NH:24][CH:25]([CH3:26])[CH3:27])=[N:22][N:23]=5)[CH:17]=4)[N:12]([S:28]([C:31]4[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=4)(=[O:29])=[O:30])[CH:11]=3)[N:7]=[C:6]([C:38]([NH2:42])=[O:39])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(C(=O)O)cc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(C(N)=O)cc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxylic acid (50 mg) was treated with HATU (51.1 mg, 0.134 mmol) followed by DMF (3 mL) and Hunig's base (0.1 mL). The reaction was stirred for 30 min at RT then treated with NH4OH (0.1 mL) and stirred for 30 min. The reaction was quenched with H2O and extracted with EtOAc (50 mL) and washed with brine (3×20 mL), dried over MgSO4, filtered and concentrated. The crude residue was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[N:4][N:3]=[N:2]1.NC1C=CC=CC=1C#N.[N-]=[N+]=[N-].[Na+].[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClCCl.N1C=CC=CC=1>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[NH:1][N:2]=[N:3][N:4]=2)=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1-c1nnn[nH]1
Agent: N#Cc1ccccc1N
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1-c1nnn[nH]1)c1ccc([N+](=O)[O-])cc1

Procedure:
3.0 g (18.6 mmol) 2-(tetrazol-5-yl)aniline (prepared by heating of 2-aminobenzonitrile in the presence of sodium azide according to E. R. Wagner, J. Org. Chem. 1973, 38, 2976) and 3.2 ml pyridine were dissolved in 50 ml dichloromethane. A solution of 3.7 g (19.9 mmol) 4-nitrobenzoyl chloride in 50 ml dichloromethane was added via a dropping funnel, and the mixture was heated with reflux for 1 h. The title compound precipitated from the solution, was filtered with suction, washed with hexane, and dried in vacuo to give a yellow powder, m.p. 223-225 (dec.)
Reaction SMILES: C([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[S:20][CH3:21])=[N:14]\[CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:8]=1[CH3:22])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[CH3:22][C:8]1[CH:9]=[C:10](/[C:13](/[S:20][CH3:21])=[N:14]/[CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH:12][C:7]=1[C:6]([OH:23])=[O:5]
Reactant: CS/C(=N/C[Si](C)(C)C)c1ccc(C(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CS/C(=N\C[Si](C)(C)C)c1ccc(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-methyl-4-{methylsulfanyl-[(E)-trimethylsilanylmethylimino]-methyl}-benzoic acid tert-butyl ester (see Example I9) (118 mg) in dichloromethane (15 ml) was added trifluoroacetic acid (0.22 ml). The reaction mixture was stirred at ambient temperature for 20 hours. Further trifluoroacetic acid (0.11 ml) was added and the mixture was stirred for another 3 hours at ambient temperature. Water was added and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 2-methyl-4-{methylsulfanyl-[(Z)-trimethylsilanyl methylimino]methyl}-benzoic acid which was used without further purification in the subsequent step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>>[CH3:17][C:18]1[N:22]([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1cncc(N[C@@H](C)c2ccccc2)n1
Yield: 10.7 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (120 mg, 0.51 mmol) and 2-methyl-benzimidazole (75 mg, 0.57 mmol) furnished the product (18 mg, 11%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=1.[OH-].[Na+]>COCCO>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][C:32]2[N:34]=[CH:12][C:9]3[CH2:8][CH2:7][C:5]4[N:6]=[C:2]([CH3:1])[S:3][C:4]=4[C:10]=3[N:33]=2)=[CH:27][CH:26]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: COc1ccc(NC(=N)N)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: COc1ccc(Nc2ncc3c(n2)-c2sc(C)nc2CC3)cn1
Temperature: 100 °C
Yield: 8.1 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 0.76 mmol), N-(6-methoxy-pyridin-3-yl)-guanidine nitrate (192 mg, 0.84 mmol), NaOH (34 mg, 0.84 mmol) and 2-methoxyethanol (2 mL) was heated at 100° C. for 24 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title product as a white solid (20 mg, 8%): mp 210-211° C. Anal. RP-HPLC: tR 11.6 min (10-70% MeCN, purity 93%). 1H-NMR (CDCl3): δ 8.42 (d, 1H, J 2.4, Ph-H), 8.26 (s, 1H, Py-H), 8.08 (dd, 1H, J 9.1, 2.9, Ph-H), 7.19 (brs, 1H, NH), 6.86 (d, 1H, J 9.1, Ph-H), 4.04 (s, 3H, OMe), 3.13 (m, 4H, CH2—CH2), 2.87 (s, 3H, CH3). 13C-NMR (CDCl3): δ 169.47, 159.97, 159.38, 159.12, 157.10, 155.16, 137.95, 131.90, 130.45, 128.62, 116.48, 110.33, 53.49, 25.29, 23.92, 19.84. MS (ESI+): m/z 326.08 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O1C(C2C=C(N[C:34]3[N:39]=[C:38]([C:40]4[C:41]([C:49]5[CH:50]=[C:51]([NH:55][C:56](=[O:63])[CH2:57][C:58]6[S:59][CH:60]=[CH:61][CH:62]=6)[CH:52]=[CH:53][CH:54]=5)=[N:42][N:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=45)[CH:37]=[CH:36][N:35]=3)C=CC=2)=CN=C1>CC(O)C.Cl.CCOC(C)=O>[F:13][C:11]([F:14])([F:12])[C:10]([N:9]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:34]2[N:39]=[C:38]([C:40]3[C:41]([C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([NH:55][C:56](=[O:63])[CH2:57][C:58]5[S:59][CH:60]=[CH:61][CH:62]=5)[CH:50]=4)=[N:42][N:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=34)[CH:37]=[CH:36][N:35]=2)[CH:3]=1)=[O:15]
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: CS(=O)(=O)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CS(=O)(=O)CCN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Temperature: 180 °C
Yield: 63 %

Procedure:
A suspension of N-[(3-aminophenyl)methyl]-2,2,2-trifluoro-N-[2-(methylsulfonyl)ethyl]acetamide (68 mg, 0.21 mmol) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (75 mg, 0.17 mmol) (see Example 2, Step B) in i-PrOH (3 mL) was acidified with 2 drops of 12 N HCl and heated in a microwave for 15 min. at 180° C. The reaction mixture was then diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 63% yield. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=6.8 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H), 7.67-7.80 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.26-7.39 (m, 4H), 7.17 (t, J=7.7 Hz, 1H), 7.05 (s, 1H), 6.94 (t, J=6.9 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.62-6.64 (m, 2H), 6.53 (s, 1H), 4.68 (s, 2H), 3.96 (s, 2H), 3.72-3.75 (m, 2H), 3.16-3.24 (m, 2H), 2.90 (s, 3H). ES-LC/MS m/z=734 [M+H]+.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([NH:14][C:15]([NH2:17])=[S:16])(=[O:13])[CH3:12]>C(O)C>[C:11]([NH:14][C:15]1[S:16][C:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:3]([NH2:4])[N:17]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)NC(N)=S
Reactant: N#CC(Br)c1ccccc1
Solvent: CCO
Product: CC(=O)Nc1nc(N)c(-c2ccccc2)s1
Yield: 23.1 %

Procedure:
α-Bromophenylacetonitrile (1.08 g, 5.48 mmol) in ethanol (10 ml) was treated with N-acetylthiourea (649 mg, 5.49 mmol) at ambient temperature for 4 hr, and then heated to reflux for 3.5 hr. The cooled mixture was concentrated in vacuo and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 2-(acetylamino)-4-amino-5-phenylthiazole (295 mg, 23%).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:27])[C:18]([OH:26])=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].Cl.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[C:34]([N:40]2[C:44]([CH3:45])=[CH:43][N:42]=[N:41]2)[CH:33]=1.C(N(CC)CC)C>C(O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:28])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:27])[C:18]=2[OH:26])=[O:23])=[C:34]([N:40]2[C:44]([CH3:45])=[CH:43][N:42]=[N:41]2)[CH:33]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Reactant: Cc1cnnn1-c1cc(F)ccc1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Temperature: 90 °C
Yield: 23.8 %

Procedure:
A mixture of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylat (30 mg, 0.076 mmol), (4-fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine, bis-hydrochloride salt (42.7 mg, 0.153 mmol) and triethylamine (0.1 ml, 0.717 mmol) in ethanol (2 mL) was heated at 90° C. for 18 h. The reaction mixture was then cooled, concentrated and purified on preparative reversed phase HPLC to afford the title compound (10 mg, 21% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 1.66-1.77 (m, 2 H) 1.90-2.01 (m, 2 H) 2.14-2.24 (m, 2 H) 2.27 (s, 3 H) 2.39-2.47 (m, 2 H) 2.50 (br. s., 1 H) 2.89 (s, 3 H) 3.19 (s, 3 H) 4.15 (d, J=3.97 Hz, 2 H) 4.23 (d, J=6.41 Hz, 2 H) 6.99 (dd, J=8.24, 2.44 Hz, 1 H) 7.26-7.33 (m, 2 H) 7.62-7.68 (m, 2 H) 8.86 (t, J=6.10 Hz, 1H) 11.73 (br. s., 1 H). LCMS (M+H)=553.22. HPLC purity: >95%.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:17]([CH2:29][CH3:30])[C:18]3[C:23]([C:24]=2[C:25]#[N:26])=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[CH:19]=3)=[CH:10][CH:9]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[CH2:29]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[CH:19]=2)[C:24]([C:25]#[N:26])=[C:16]1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:9][CH:10]=1)[CH3:30]
Reactant: CCn1c(C#Cc2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(C#Cc2ccc(N3CCNC3=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
1-(2-Chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (55 mg, 0.13 mmol), prepared as in Example 1AC, is combined with K2CO3 (50 mg, 0.36 mmol) and DMF (550 μL). This mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted in EtOAc, and is washed with H2O, and then with brine. The organic layer is dried and concentrated. Purification by silica chromatography (10-50%, EtOAc/CH2Cl2) yields 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (47 mg, 94%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([F:24])([F:23])([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([F:24])([F:20])([F:21])([F:22])[F:23])=[CH:15][CH:14]=1)=[O:9]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Stage 185.2 using 5-Bromo-6-chloro-nicotinic acid and 4-aminophenylsulfur pentafluoride to afford an orange solid. HPLC (Condition 4), tR=6.43 min, UPLC-MS (Condition 3) tR=1.27 min, m/z=435.3/437.2.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25](=[O:27])[CH3:26])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10][C:9]=1I.C(N(CC)CC)C>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25](=[O:27])[CH3:26])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:12][C:13]=1[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(C#C[Si](C)(C)C)c1
Reaction time: 12 h

Procedure:
Trimethylsilylacetylene (114 il) was added to a degassed solution of ethyl N-[(4-chloro-3-iodophenyl) methyl]-5-acetoxyindole-2-carboxylate (0.2 g), bis(triphenylphosphine)palladium (II) chloride (2 mg), triethylamine (56 il) and copper (I) iodide (1 mg) in acetonitrile and the mixture was stirred under an argon atmosphere for 12 hours. A further aliquot of bis(triphenylphosphine)palladium (II) chloride (2 mg) and trimethylsilylacetylene (114 il) was added and stirring continued for 2 hours. A further aliquot of trimethylsilylacetylene (114 il) was added and stirring was continued for 12 hours. A small amount of silica was added to the reaction mixture and the solvent was evaporated. The residue was added to a 5 g silica Isolute column and eluted with an ethyl acetate iso-hexane mixture (1:4) to give the title compound as a colourless oil (0.15 g). NMR (CD3SOCD3): d 0.0 (s, 9H), 1.1 (t, 31H), 2.1 (s, 3H), 4.1 (m, 2H), 5.6 (s, 2H), 6.7 (m, 2H), 6.9 (m, 2H), 7.1 (m, 1H), 7.2 (m, 2H), 7.3 (n, 1H), 7.4 (m, 1H); m/z 468.5 (M+H).