Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([NH:8][C:9]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[N:10][NH2:11])[CH:7]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].[K+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([N:8]2[C:9]([C:12]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:13]=3)=[N:10][NH:11][C:28]2=[O:29])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1NC(=NN)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-n1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n[nH]c1=O
Temperature: 24 °C
Reaction time: 18 h

Procedure:
N-(5-Chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl) benzene carbohydrazonamide (4 g, 9.7 mmol) was taken up in THF (600 ml) under N2.and 1,1'-carbonyldiimidazole (1.9 g, 11.72 mmol) added. The solution was stirred for 18 h at 24° C. before solvent was removed by rotary evaporation. The residue was taken up in ethyl acetate (400 ml) and washed with 0.1N HCl solution (100 ml), water (100 ml) and brine prior to drying over MgSO4. Recrystallization from acetonitrile gave 2.92 g (68.6%) mp 205.5-207° C. IR(KBr, υ=cm-1) 3170, 3057, 1726, 1504, 1277, 1128; 1H NMR (300 MHz, DMSO-d6) δ 3.48 (3H, s), 7.15 (1H, d, J=9.0 Hz), 7.55 (1H, dd, J=8.9 Hz, 2.6Hz), 7.69 (1H, d, J=2.6 Hz), 7.87 (2H, br.s), 8.17 (1H, br.s), 12.50 (1H, br.s); MS(DCl)mtz: 438(MH+).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:14][N:13]=[C:12]([NH:15][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:57]([O:61][C:62](=[O:68])[NH:63][CH2:64][CH2:65][CH2:66][OH:67])([CH3:60])([CH3:59])[CH3:58].C(=O)([O-])N>C1COCC1>[C:22]([C:19]1[N:20]=[CH:21][C:16]([NH:15][C:12]2[CH:11]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[O:67][CH2:66][CH2:65][CH2:64][NH:63][C:62](=[O:68])[O:61][C:57]([CH3:60])([CH3:58])[CH3:59])[NH:14][N:13]=2)=[N:17][CH:18]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COc1cccc(O)c1-c1cc(Nc2cnc(C#N)cn2)n[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OCCCNC(=O)OC(C)(C)C)c1-c1cc(Nc2cnc(C#N)cn2)n[nH]1
Temperature: 0 °C
Reaction time: 0.06 h
Yield: 44.2 %

Procedure:
A 5 L flange-neck round-bottom flask equipped with an air stirrer rod and paddle, thermometer, pressure-equalizing dropping funnel, and nitrogen bubbler is charged with 5-(5-(2-hydroxy-6-methoxy-phenyl)-1H-pyrazol-3-ylamino)-pyrazine-2-carbonitrile (47.0 g, 152 mmol) and anhydrous THF (1.2 L). The stirred suspension, under nitrogen, is cooled to 0° C. A separate 2 L 3-necked round-bottom flask equipped with a large magnetic stirring bar, thermometer, and nitrogen bubbler is charged with triphenylphosphine (44.0 g; 168 mmol) and anhydrous THF (600 mL). The stirred solution, under nitrogen, is cooled to 0° C. and diisopropylazodicarboxylate (34.2 g; 169 mmol) is added and a milky solution is formed. After 3-4 min, a solution of t-butyl-N-(3-hydroxypropyl)-carbamate (30.3 g, 173 mmol) in anhydrous THF (100 mL) is added and the mixture is stirred for 3-4 min. This mixture is then added over 5 min to the stirred suspension of starting material at 0° C. The reaction mixture quickly becomes a dark solution and is allowed to slowly warm up to room temperature. After 6.5 h, more reagents are prepared as above using PPh3 (8 g), DIAD (6.2 g) and carbamate (5.4 g) in anhydrous THF (150 mL). The mixture is added to the reaction mixture, cooled to −5° C. and left to warm up to room temperature overnight. The solvent is removed in vacuo. The resulting viscous solution is loaded onto a pad of silica and product is eluted with ethyl acetate. The concentrated fractions are separately triturated with methanol and resulting solids are collected by filtration. The combined solids are triturated again with methanol (400 mL) and then isolated by filtration and dried in vacuo at 50° C. overnight to give 31.3 g of desired product. LC-ES/MS m/z 466.2 [M+1]+.
Reaction SMILES: CC(C)([O-])C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O.CO>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][C:17]#[N:18])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C=O)cc1Cl
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC#N)cc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a suspension of potassium tert-butoxide (2.36 g, 20 mmol, 4 eq.) in THF (15 mL), a solution of tosylmethyl isocyanide (1.95 g, 10 mmol, 2 eq.) in THF (5 mL) was added at −78° C. The mixture was stirred at −78° C. for 15 min. A solution of 3-chloro-4-methoxybenzaldehyde (879 mg, 5 mmol, 1 eq.) in THF (5 mL) was added dropwise. The resulting mixture was stirred for 1.5 hours at −78° C. To the cooled reaction mixture, methanol (5 mL) was added. The mixture was then heated at reflux for 30 min. The solvent was removed in vacuo. The residue was partitioned between water (20 mL) and AcOEt (10 mL). The aq. phase was extracted with AcOEt (2×10 mL). The comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 50 fractions of 45 mL, Heptane to Heptane+25% AcOEt) to yield (3-chloro-4-methoxy-phenyl)-acetonitrile as a pale yellow oil that solidified upon standing.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>O1CCOCC1>[OH:30][C@:26]([C:23]1[CH:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: COC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Solvent: C1COCCO1
Product: COC(=O)c1nc2c(s1)CCOc1ccc(C#C[C@@](C)(O)c3cc(C)on3)cc1-2

Procedure:
Methyl 9-bromo-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (0.2 g) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure F but substituting CuI for ZnBr and Dioxane as the solvent to afford 70 mg of methyl 9-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate following reverse phase hplc purification. MS (Q1) 411.2 (M)+. Methyl 9-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (70 mg) was saponified with LiOH in THF/water followed by similar to as described in Example 2 to afford 39.7 mg of 9-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide following reverse phase hplc purification. MS (Q1) 396 (M)+. 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=2.1 Hz, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.31 (dd, J=8.3, 2.2 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.46 (s, 1H), 6.36 (s, 1H), 4.35 (t, J=4.9 Hz, 2H), 3.41 (t, J=4.9 Hz, 2H), 2.41 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:15][CH2:16][CH2:17][CH2:18][O:19][NH2:20])(=[O:10])=[O:9])[CH:7]=1.Cl.[N:28]1([C:33](N)=[NH:34])C=CC=N1>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:15][CH2:16][CH2:17][CH2:18][O:19][NH:20][C:33]([NH2:34])=[NH:28])(=[O:10])=[O:9])[CH:7]=1
Reactant: N=C(N)n1cccn1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCON)c1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
A mixture of 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyamine (265 mg, 0.66 mmol, prepared in the preceding step) and 1H-pyrazole-1-carboxamidine hydrochloride (196 mg, 1.33 mmol) in anhydrous N,N-dimethylformamide (3 mL) was stirred at ambient temperature for 2.5 h. Additional 1H-pyrazole-1-carboxamidine hydrochloride (97 mg, 0.66 mmol) was added and the reaction was stirred at ambient temperature for 3 days. N,N-Dimethylformamide was removed in vacuo, then acetonitrile (1 mL) was added to precipitate excess 1H-pyrazole-1-carboxamidine hydrochloride. The mixture was filtered and the filtrate was concentrated in vacuo. The residual oil was partitioned between diethyl ether (20 mL) and water (20 mL). The aqueous layer was washed with diethyl ether (2×20 mL). The aqueous layer was neutralized (pH 7) with 2N NaOH and extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with pH 7 buffer (2×20 mL) and brine (30 mL), dried over Na2SO4, filtered, and evaporated to give the free base of the title compound (281 mg, 96%) as a colorless oil. Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H22CIN3O6S: 444.1 (M+H), 466.1 (M+Na). Found 444.6, 466.7.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)=[O:5].O1CCOCC1.Cl>O1CCOCC1>[ClH:1].[NH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: NCCNC(=O)c1ccccc1Cl
Temperature: 25 °C

Procedure:
tert-Butyl {2-[(2-chlorobenzoyl)amino]ethyl}carbamate was dissolved in dioxane and a 4M hydrogen chloride dioxane solution was added thereto. The whole was stirred at room temperature to obtain N-(2-aminoethyl)-2-chlorobenzamide hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[Cl:19].[Li]CCCC.[CH3:25][C:26]1[S:27][C:28]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[C:29]([CH3:31])[N:30]=1.C(=O)=O.CC(C)=O>C1COCC1>[Cl:12][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([Cl:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:32]([C:28]3[S:27][C:26]([CH3:25])=[N:30][C:29]=3[CH3:31])([OH:36])[CH:33]([CH3:35])[CH3:34])[CH:3]=2)[N:8]=1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1
Reactant: Cc1nc(C)c(C(=O)C(C)C)s1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(O)(c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)C(C)C)s1
Temperature: -75 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-2,4-dichloro-3-phenylquinoline (275 mg, 0.78 mmol, Intermediate 1: step c) was added THF (10 mL) to give a homogeneous clear solution. The solution was cooled in a dry ice—acetone bath and n-BuLi (2.5 M in hexanes, 0.28 mL, 0.7 mmol) was added which resulted in an immediate orange-brown homogeneous solution. After 2 minutes, a solution of 1-(2,4-dimethylthiazol-5-yl)-2-methylpropan-1-one (200 mg, 1.09 mmol, Intermediate 4: step b) in 3 mL THF was added. The reaction mixture was maintained at −75° C. for 5 minutes then the dry ice—acetone bath was replaced with a 0° C. ice-bath. After 20 minutes the ice-bath was removed and the mixture was stirred at room temperature for 20 minutes. The mixture was quenched after a total reaction time of 45 minutes with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (100% DCM increasing to 20% EtOAc/DCM) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CD2Cl2) δ 8.42 (d, J=1.9 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.9, 2.1 Hz, 1H), 7.57-7.46 (m, 3H), 7.41-7.27 (m, 2H), 2.77 (p, J=6.6 Hz, 1H), 2.52 (s, 3H), 2.19 (s, 3H), 1.16 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H); MS (ESI): mass calcd. for C24H22Cl2N2OS, 456.1, m/z found 457.0 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl[CH2:20][O:21][CH2:22][CH2:23][Cl:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:24][CH2:23][CH2:22][O:21][CH2:20][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: ClCCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(COCCCl)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A solution of benzyl 4-cyanopiperidine-1-carboxylate (10.0 g, 41 mmol) and 2-chloroethyl chloromethyl ether (6.3 mL, 49.2 mmol) in THF (80 mL) was cooled to −78° C. To this solution was added drop wise LiHMDS (50 mL, 50 mmol, 1N in THF) and the resulting mixture was gradually warmed to room temp over 5 h. The reaction was quenched with water and the organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (1:1 EtOAc/hexane) to give the title compound as yellow oil (11.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ: 7.33-7.31 (5H, m), 5.10 (2H, d, J=5.9 Hz), 4.21 (2H, bs), 3.79-3.76 (2H, m), 3.63-3.60 (2H, m), 3.52-3.51 (2H, m), 3.09 (2H, bs), 1.96-1.92 (2H, m), 1.55-1.51 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[O:7][CH:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1.[Ni]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][CH:8]([O:7][C:6]1[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[NH2:17])[CH3:15])[CH3:14]
Reactant: CCOC(=O)CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)Oc1cc(F)ccc1N

Procedure:
To a solution of Ethyl 3-(5-fluoro-2-nitrophenoxy)butanoate (1.3 g) in THF (50 ml) was added Raney nickel (150 mg) and the reaction mixture was hydrogenated. The catalyst was filtered off and the filtrate was concentrated in vacuo.
Reaction SMILES: C(OC([N:8](C)[C@@H:9](CC(C)(C)C)[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[F:37][C:20]([F:19])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:10](=[O:11])[CH2:9][NH2:8])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:25][CH:26]=1
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: NCC(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-L-glycine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.27 (d, J=6.9, 1H), 7.58 (d, J=8.7, 2H), 6.61 (d, J=8.7, 2H), 4.39-4.29 (m, 1H), 3.57 (s, 2H), 3.51 (dd, J=10.2, 3.4, 1H), 3.30 (dd, J=10.0, 7.9, 1H), 3.20 (dd, J=9.6, 8.4, 1H), 3.00 (dd, J=9.9, 4.2, 1H), 2.69 (ddd, J=16.0, 8.3, 4.3, 1H), 2.66-2.59 (m, 1H), 2.51-2.17 (bs, 2H), 2.11-2.01 (m, 1H), 1.91 (dtd, J=13.0, 7.9, 5.0, 1H), 1.61 (dq, J=12.6, 8.0, 1H), 1.41-1.29 (m, 1H); MS (ESI+) m/z 328 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=O)[CH:6]=[N:5]1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:18]([CH:21]=1)[C:19]#[N:20].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:10]([C:7]2[CH:6]=[N:5][N:4]([CH2:3][CH2:2][OH:1])[C:8]=2[CH3:9])=[O:12])[CH:15]=[CH:16][C:17]=1[O:22][CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])#[N:20]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1c(C(=O)O)cnn1CCO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1CCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.9 %

Procedure:
1-(2-Hydroxyethyl)-5-methylpyrazole-4-carboxylic acid (1.7 g), 5-amino-2-neopentyloxybenzonitrile (2.1 g), 1-hydroxybenzotriazole (1.6 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.3 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 5 h. The reaction mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:chloroform:methanol=100:1). Diisopropyl ether was added to the obtained oily substance to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give the title compound (1.1 g), melting point: 98–100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([N:13]1[CH2:14][CH2:15][CH:10]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:11][CH2:12]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A solution of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine (3.21 g, 0.0106 mol), triethylamine (2.5 g, 0.025 mol), and benzoyl chloride (1.70 g, 0.012 mol) in 400 mL of methylene chloride was stirred 16 h at room temperature. The reaction was concentrated to dryness and dissolved in chloroform. The chloroform layer was extracted successively with water, 1N sulfuric acid, and 5% sodium hydroxide. The chloroform layer was dried (Na2SO4) and filtered. The chloroform was removed to give a fluffy-white residue. This material was dissolved in methylene chloride and chromatographed by flash chromatography on silica gel. Elution was accomplished using methylene chloride, 1% acetone-methylene chloride, 2% acetone-methylene chloride, and 4% acetone-methylene chloride. Fractions of similar purity were combined, and solvents removed to give a fluffy-white residue. This material was triturated with isopropyl ether and chilled in a freezer. A white solid was isolated and dried, 16 h at 78° C. This furnished 1.40 g (32.5%) of white crystalline solid, mp 157°-158° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:43][C:26]([CH3:42])([CH3:25])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:30]=[N:29]1
Reactant: CC(C)n1c(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n[nH]c1=O
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)n1c(-c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)n[nH]c1=O

Procedure:
Similarly to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-one was reacted with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 447. LCMS: 467.1. 1H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 8.25 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.43 (dd, J=8.3, 1.8 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 5.35-5.18 (m, 1H), 4.71 (s, 1H), 4.37 (t, J=5.0 Hz, 2H), 4.03 (s, 2H), 3.39 (dd, J=17.6, 12.4 Hz, 2H), 1.56 (d, J=6.9 Hz, 6H), 1.09 (s, 6H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23](I)[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:34][CH2:35][O:36][CH2:37][CH:38]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.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]>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23]([C:33]4[CH2:38][CH2:37][O:36][CH2:35][CH:34]=4)[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CC1c1nn2c(I)ncc2c(=O)[nH]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccccc2)CC1c1nn2c(C3=CCOCC3)ncc2c(=O)[nH]1
Temperature: 150 °C
Yield: 55.5 %

Procedure:
To a mixture of compound 6 (100 mg, 0.23 mmol) and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (145 mg, 0.69 mmol) in DMF (10 mL) was added potassium phosphate (146 mg, dissolved in 1 mL of H2O). The reaction mixture was degassed by purging with N2 for 15 min, before Pd(dppf)2Cl2 (28 mg, 0.035 mmol) and Xantphos (40 mg, 0.069 mmol) were added. The resulting suspension was bubbled with nitrogen for 10 minutes. The reaction mixture was heated to 150° C. under microwave irradiation for one hour. After cooling down, the reaction mixture was diluted with EtOAc (50 mL), and the precipitate was filtered off. The filtrate was washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (eluting with EtOAc) to afford 7 (50 mg, 55% yield) as a white solid. LC-MS: m/z 393.03 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.37˜7.22 (m, 6H), 4.40 (d, J=2.8 Hz, 2H), 3.95˜3.92 (m, 2H), 3.82˜3.79 (d, J=12.6 Hz, 1H), 3.61˜3.58 (d, J=12.6 Hz, 1H), 3.39˜3.37 (m, 1H), 3.00˜2.98 (d, J=10.0 Hz, 1H), 2.76˜2.73 (m, 3H), 2.54˜2.52 (m, 1H), 2.44˜2.42 (m, 1H), 1.95˜1.90 (m, 2H), 1.21 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18]>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([NH:8][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:18]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1cc(Cl)ncn1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)ncn1)Nc1ccccc1Cl
Temperature: 25 °C
Yield: 174.3 %

Procedure:
A solution of 6-chloro-pyrimidin-4-ylamine (997 mg, 7.7 mmol) and 2-chlorophenyl isocyanate (0.46 mL, 3.85 mmol) in THF (20 mL) is refluxed for 4 h. A further amount of 2-chlorophenyl isocyanate (0.46 mL, 3.85 mmol) is added and the reaction mixture is refluxed for 28 h. The reaction mixture is cooled to RT, the precipitate is filtered to afford the title compound (1.9 g, 86%).