Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[NH2:60][C@H:61]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68].Cl>ClCCl>[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10]([NH:60][C@H:61]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:67]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:68])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of Fmoc-Phe-OH (6, 5.00 g, 12.9 mmol) in dichloromethane (100 mL) were added HOSu (1.56 g, 13.6 mmol) and DCC (2.93 g, 14.2 mmol). The resulting suspension was stirred at room temperature for 3 h. Then, triethylamine (1.83 mL, 13.2 mmol) and H-Lys(Boc)-OtBu.HCl (4.46 g, 13.2 mmol) were added consecutively, and the resulting suspension was stirred overnight. The reaction mixture was filtered, and the filtrate was washed with 10% aqueous citric acid, water, a saturated aqueous NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. This gave crude 8 (8.97 g, max. 12.91 mmol, 100%) as a white solid. 1H NMR (300 MHz, CDCl3) δ: 1.10-1.90 (m, 6H, CH2-Lys), 1.41 (s, 18H, tBu), 3.01-3.15 (m, 4H, N—CH2-Lys+CH2-Phe), 4.19 (t, 1H, J=6.8 Hz, CH-Fmoc), 4.25-4.55 (m, 4H, 2×α-H+ CH2-Fmoc), 7.19-7.35 (m, 7H, HAr), 7.38 (t, 2H, J=7.4 Hz, HAr), 7.51 (m, 2H, HAr), 7.72 (d, 2H, J=7.5 Hz, HAr).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[CH3:28][N:29](C)C=O>C(OCC)(=O)C.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.[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:3][C:2]([C:28]#[N:29])=[CH:7][N:6]=1)(=[O:11])=[O:10]
Reactant: CN(C)C=O
Reactant: O=S(=O)(Nc1ncc(Br)nc1OCc1cccnc1)c1cccc(Cl)c1Cl
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: CCOC(C)=O
Product: N#Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1
Reaction time: 5 h

Procedure:
N-[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide (Example 34) (0.15 g), tetrakis(triphenylphosphine)palladium(0) (0.04 g) and zinc cyanide (0.03 g) in N,N-dimethylformamide (5.0 mL) was heated at 70° C. After 5 h, the mixture was diluted with ethyl acetate (30 mL) and washed with 5% aqueous citric acid (5 mL), dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures containing 1% acetic acid gave the title compound as a white solid (0.058 g).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.OS(O)(=O)=O>>[NH:5]1[CH:6]=[CH:7][CH2:2][CH2:3][CH:4]1[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][N:5]=1
Reactant: OC1CCNCC1
Agent: O=S(=O)(O)O
Product: C1=CNC(c2ccccn2)CC1

Procedure:
2-(Piperidinyl)pyridines 83 are prepared as described in Scheme 22. Strong base, such as n-BuLi, in a solvent such as dry THF, is added to dibromopyridine 77 at a temperature less than RT, preferably below about −50° C., more preferably at about −70° C. 4-Methylpiperidone is added to form the 4-hydroxy-piperidine 80 at a temperature less than RT, preferably below about −50° C., more preferably at about −70° C. The 4-hydroxy piperidine 80 is hydrated, such as with strong acid, preferably H2SO4, at a temperature above RT, preferably above 750C, more preferably at about 100 C., to form the tetrahydro-bipyridine 81. The 2-bromo-pyridine 81 is aminated, such as with NH4OH, in the presence of Cu powder at a temperature above RT, preferably above about 75° C., more preferably at about 100° C., to form the amino-pyridine 82. Preferably the reaction is run in a sealed tube. The 1′,2,3′,6′-tetrahdyro-[2,4′]bipyridinyl-6-ylamine is hydrogenated, such as with H2 in the presence of Pd(OH)2/C, at a temperature of about RT, to form the piperidinyl pyridine 83.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)c1cc2c(cc1Cl)NCC2
Yield: 71.5 %

Procedure:
6-Chloro-5-tert-butylindole (D55) (0.29 g, 1.40 mmol) was treated with sodium cyanoborohydride as in the method of Description 10 to give the title compound (0.21 g, 72%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[C:6]2([CH3:14])[CH3:13].[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C.O>[CH3:13][C:6]1([CH3:14])[C:7]2[C:3](=[C:2]([O:1][C:18](=[O:19])[NH:17][CH3:16])[C:10]([CH3:11])=[CH:9][C:8]=2[CH3:12])[CH2:4][CH:5]1[CH3:15]
Reactant: Cc1cc(C)c2c(c1O)CC(C)C2(C)C
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)Oc1c(C)cc(C)c2c1CC(C)C2(C)C
Temperature: 70 °C
Yield: 63.7 %

Procedure:
34 g of 4-hydroxy-1,1,2,5,7-pentamethyl-indane, 14.3 g of methyl isocyanate and a few drops of triethylamine were dissolved in 102 ml of ligroin and the solution was stirred under slight reflux (about 70° C.) overnight. After cooling to 30° C., the mixture was stirred with 40 ml of water and the colorless crystals were filtered off and dried. Recrystallization from ligroin and toluene gave 27.7 g of N-methyl-carbamic acid 1,1,2,5,7-pentamethylindan-4-yl ester of melting point 130.5°-131° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:2]1.Cl[C:15]1[N:16]=[N:17][C:18]([C:21]2[O:25][N:24]=[C:23]([CH3:26])[N:22]=2)=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:26][C:23]1[N:22]=[C:21]([C:18]2[N:17]=[N:16][C:15]([N:1]3[CH2:5][CH2:4][C:3]4([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][CH2:6]4)[CH2:2]3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)OCC21CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccc(N3CCC4(COc5ccccc54)C3)nn2)n1
Yield: 47.2 %

Procedure:
A solution (5 ml) of spiro[1-benzofuran-3,3′-pyrrolidine] (50 mg) obtained in Example 50-(5) and 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (56 mg) obtained in Example 43-(2) and potassium carbonate (79 mg) in N,N-dimethylformamide was stirred at 95° C. for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate to give the object product (45.1 mg, 47%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=CC=C[CH:2]=1.[N:11]1[CH:12]=[N:13][N:14]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]([C:24]3[S:25][C:26]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[O:23])[CH:17]=[CH:16][C:15]=12.N1C=CN2C=CC(CNC(=O)C3C=CC(C4CCNCC4)=CC=3)=CC=12>>[CH3:2][CH:1]([S:7]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[S:25][C:24]([C:22]([NH:21][CH2:20][C:18]3[CH:17]=[CH:16][C:15]4[N:14]([N:13]=[CH:12][N:11]=4)[CH:19]=3)=[O:23])=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)(=[O:9])=[O:8])[CH3:6]
Reactant: O=C(NCc1ccc2ncnn2c1)c1ccc(C2CCNCC2)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Product: CC(C)S(=O)(=O)N1CCC(c2ccc(C(=O)NCc3ccc4ncnn4c3)s2)CC1

Procedure:
The title compound was prepared as described in Example 682, substituting propane-2-sulfonyl chloride for benzenesulfonyl chloride and N-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-5-(piperidin-4-yl)thiophene-2-carboxamide for N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (t, J=5.8 Hz, 1H), 8.86 (d, J=1.5 Hz, 1H), 8.48 (s, 1H), 7.83 (dd, J=9.1, 0.9 Hz, 1H), 7.64 (m, 2H), 6.97 (dd, J=3.7, 0.9 Hz, 1H), 4.53 (d, J=5.8 Hz, 2H), 3.71 (m, 2H), 3.25 (m, 1H), 3.02 (m, 3H), 2.00 (m, 2H), 1.56 (m, 2H), 1.22 (d, J=6.8 Hz, 6H); MS (ESI(+)) m/e 448 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.O>CS(C)=O.O1CCCC1>[O:9]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:4]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 0.5 h

Procedure:
Sodium hydride (6.63 g, 60% in mineral oil) was added to trimethylsulfoxonium iodide (36.5 g) in dimethyl sulfoxide (150 mL) and tetrahydrofuran (150 mL), was and stirred for 30 minutes. tert-Butyl 4-oxopiperidine-1-carboxylate (25.4 g) was added and the reaction was stirred for 3 hours. The reaction was poured into water (800 mL) and extracted three times with ether. The combined extracts were washed three times with water, and brine, dried over Na2SO4, filtered, and concentrated to yield the crude product which was used without further purification.
Reaction SMILES: N(/C(C)(C)C#N)=N\C(C)(C)C#N.[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[O:18][CH2:17]2.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([Br:13])[CH:15]=2)[C:19](=[O:23])[O:18]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2cc(Br)ccc21
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2cc(Br)ccc21

Procedure:
5-bromoisobenzofuran-1(3H)-one (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.540 g, 3.29 mmol) and 1-bromopyrrolidine-2,5-dione (5.85 g, 32.86 mmol) were dissolved CCl4 and heated at reflux for 2 hours. The reaction was cooled and filtered, the filtrate was evaporated to afford the desired material, as a yellow solid (6.05 g, 63.1% yield), which was used directly in the next stage.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)=O.FC(F)(F)C([O-])=O.[NH4+:31].O>C(Cl)Cl>[C:18]1([CH2:17][N:13]2[CH2:14][CH2:15][O:16][CH:11]([C:9]3[NH:8][C:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=4[N:31]=3)[CH2:12]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N[C@@H]1CCCCC1=O)C1CN(Cc2ccccc2)CCO1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1ccc(CN2CCOC(c3nc4c([nH]3)CCCC4)C2)cc1
Temperature: 150 °C
Yield: 75.4 %

Procedure:
A mixture of N-[(1R)-2-oxocyclohexyl]-4-(phenylmethyl)-2-morpholinecarboxamide (1.1 g, 3.48 mmol) and ammonium trifluoroacetate (2.069 g, 17.38 mmol) was heated at 150° C. for 20 minutes. After cooling, to the mixture was added water (30 mL) and CH2Cl2 (50 mL). The organic layer was separated and washed with brine, dried (MgSO4), and concentrated to afford the crude title compound (0.78 g). LC-MS (ES) m/z=298 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[N:7](COCC[Si](C)(C)C)[CH:6]=[C:5]2[C:43]#[N:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:43]#[N:44]
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(C#N)c[nH]c12
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A solution of (±)-tert-butyl 4-((1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (406 mg, 0.632 mmol) and TBAF (4 mL, 4.00 mmol) (1M in THF) in THF (10 mL) was heated at reflux for 8 hours then cooled to ambient temperature and the solvent was evaporated. Purified on SiO2 column with 50% ethyl acetate/hexanes to obtain (±)-tert-butyl 4-((1-(5-chloro-3-cyano-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (231 mg, 0.451 mmol, 71.4% yield) as a clear foam. 1H-NMR (CDCl3, 400 MHz) δ 8.11 (bs, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.27 (m, 2H), 7.11 (m, 2H), 7.10 (s, 1H), 4.54 (q, J=6.5 Hz, 1H), 3.7 (m, 2H), 3.43(d, J=8.8 Hz, 1H), 3.20 (d, J=8.6 Hz, 1H), 3.10 (t, J=7.5 Hz, 1H), 2.97 (t, J=10.1 Hz, 1H), 2.38 (m, 2H), 1.80-2.00 (m, 2H), 1.64 (m, 1H), 1.40 (s, 3H). LC/MS (HPLC method 4): tR=4.02 min, 534.13(MNa)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([CH3:13])=[CH2:12])[C:9]=1[Cl:10])[C:5]#[N:6].Cl[C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].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>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:10][C:9]1[C:8]([C:11]([CH3:13])=[CH2:12])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1
Reactant: C=C(C)c1cc(C#N)cc(N)c1Cl
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C=C(C)c1cc(C#N)cc(Nc2nc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 100 °C
Yield: 76.6 %

Procedure:
A mixture of 3-amino-4-chloro-5-(prop-1-en-2-yl)benzonitrile (367 mg, 1.91 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (676 mg, 1.91 mmol), Cs2CO3 (1.24 gm, 3.81 mmol), DPPF (106 mg, 0.191 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (110 mg, 0.191 mmol) and Pd(OAc)2 (128 mg, 0.572 mmol) in a microwave vial that was flushed with nitrogen. Dioxane (16 mL) was added and the vial was sealed and heated at 100° C. for 4 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed from the filtrate and radial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc afforded 2-((2-chloro-5-cyano-3-(prop-1-en-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (748 mg) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH2:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.P(=O)(O)(O)O.[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>C(O)(=O)C.CO.CCOCC.C(OCC)(=O)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[C:19]1([CH2:18][N:25]2[CH2:26][CH:27]=[C:28]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[C:6]([C:10]([NH2:12])=[O:11])[CH:5]=4)[NH:1][CH:2]=3)[CH2:29][CH2:30]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: N
Agent: O=C(O)/C=C\C(=O)O
Agent: O=P(O)(O)O
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1
Reaction time: 18 h

Procedure:
A suspension of 1H-indole-5-carboxamide (0.4 g) in galcial acetic acid (20 ml) was heated to 80°under nitrogen, and the resulting solution was treated with aqueous phosphoric acid (2N; 7 ml). Freshly distilled 1-benzyl-4-piperidone (1.4 g) in glacial acetic acid (5 ml) was added and the reaction mixture was stirred at 70° for 18 h, cooled, and poured into a mixture of ice and 0.88 ammonia solution (50 ml) with ice bath cooling. Ethyl acetate (50 ml) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (4×60 ml), and the combined organic extracts were dried (MgSO4) and evaporated to dryness. The resulting oil was chromatographed on Merck Kieselgel 60 (100 g) eluting with 10% methanol in ethyl acetate. Evaporation of the solvent gave a foam which was treated with maleic acid in methanol/ether to give the title compound as microcrystals (0.19 g), m.p. 164°-166°.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:9](OC)(OC)[O:10][CH3:11].C(OC(=O)C)(=O)C>>[CH3:9][O:10][CH:11]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(OC)OC
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC=CC(=O)CC(=O)OC

Procedure:
From methyl acetoacetate (30.2 g, 0.26 mol), trimethyl orthoformate (26.7 g, 0.18 mol) and acetic anhydride (53 g., 0.52 mol): 4.3 g, 15%; bp=100°-105° C. at 0.5 mm Hg (lit.1 80°-84° C. at 0.15 mm Hg); NMR (CDCl3) δ 2.4 (d, 3H), 3.8 (d, 3H), 4.1 (s, 3H), 7.6 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([C:23](=[O:26])[NH:24][N:25]=2)[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].[CH3:27]NN>C(#N)C>[CH3:27][N:24]1[C:23](=[O:26])[N:5]2[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:2]([CH3:1])[N:3]=[C:4]2[NH:25]1
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2c(n[nH]c2=O)N1
Reactant: CNN
Solvent: CC#N
Product: CC(C)OC(=O)C1=C(c2cccc([N+](=O)[O-])c2)N2C(=O)N(C)NC2=NC1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
The title B compound of Example 1 (1 g, 2.0 mmol) in acetonitrile (7 ml) was cooled to 0° C. under argon and was treated with methylhydrazine (0.125 mL, 3.2 mmol). The reaction turned yellow instantaneously and a light yellow solid precipitated out. The reaction was allowed to stir at room temperature for 45 minutes and the solid was then filtered off and washed with acetonitrile to provide the title compound (620 mg) as a light yellow solid, m.p. 255°-256° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][C:19]2[N:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=2)=[CH:13][C:12]=1[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:28].C(O)(C)C>>[CH2:1]([O:8][C:9](=[O:27])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][C:19]2[N:24]=[CH:23][N:22]=[C:21]([NH2:28])[CH:20]=2)=[CH:13][C:12]=1[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(Nc1cc(F)c(Oc2cc(Cl)ncn2)cc1F)OCc1ccccc1
Solvent: CC(C)O
Product: Nc1cc(Oc2cc(F)c(NC(=O)OCc3ccccc3)cc2F)ncn1
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of benzyl[4-(4-chloropyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (3.92 g) and 2M ammonia-isopropanol (50 ml) was heated at 120° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to room temperature, then concentrated under reduced pressure. The resultant residue was partitioned between ethyl acetate and a 10% aqueous solution of potassium bisulfate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale yellow crystals (561 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.C[N:37](C)C=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:37])=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
In a solution of 0.80 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methoxymethyl benzoic acid in 30 mL of dichloromethane, 0.23 g of oxalyl chloride and 0.06 g of N,N-dimethylforamide were added, and stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, the resudue was dissolved in 5 mL of tetrahydrofuran, and a solution of 1.50 g of concentrated ammonia water in 10 mL of tetrahydrofuran was added dropwise at room temperature with stirring. After the completion of the addition dropwise, it was continued to stir further for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 mL of water was added in the residue, and extracted with ethyl acetate (20 mL×1). The organic phase was washed with 10 mL of 2N hydrochloric acid, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:1) to obtain 0.34 g of the aimed product as white crystal.
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.[Br-].[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[Zn+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:4]3[S:5][CH:6]=[C:2]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)[C:3]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: [Zn+]c1nccs1
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3scc(-c4nccs4)c3C)c(C)nc12
Temperature: 65 °C
Yield: 75 %

Procedure:
To a flask containing 3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 0.64 mmol) and PdCl2(dppf) (0.023 g, 0.032 mmol) is added a 0.5 M solution of 2-thiazolylzinc bromide (3.82 mL, 1.91 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (25 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (15%-20% EtOAc gradient) furnish the title compound (0.19 g, 0.48 mmol, 76%). 1H NMR (CDCl3) δ 0.88 (t, J=7.5 Hz, 6H), 1.75-1.92 (m, 4H), 2.36 (s, 3H), 2.47 (s, 3H), 2.50 (, 3H), 3.29-3.39 (m, 1H), 6.69 (s, 1H), 7.33 (d, J=3.3 Hz, 1H), 7.89 (d, J=3.3 Hz, 1H), 7.99 (s, 1H). LC/MS (m/z): calcd. for C21H24N4S2 (M+H)+: 397.2; found: 397.3.