Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([OH:16])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[CH3:19][O:20][C:21](=[O:33])[CH:22]([NH2:32])[CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1C=C2C(N(O)N=NC2=CC=1)=O.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:33])[CH:22]([NH:32][C:14](=[O:16])[CH2:13][C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:18][CH:17]=2)[CH:9]=[N:10][CH:11]=1)[CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26]
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1
Reactant: COC(=O)C(N)CNC(=O)OC(C)(C)C
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(CNC(=O)OC(C)(C)C)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid (607 mg, 1.64 mmol), 3-t-Butoxycarbonylamino-2(RS)-aminopropionic acid methyl ester (352 mg, 1.61 mmol), HOOBT (319 mg, 1.96 mmol), and triethylamine (0.54 ml, 3.87 mmol) in DMF (13 ml) at 0° C., was added EDC (2.67 g, 13.9 mmol). The reaction was stirred at room temperature for 18 hrs, diluted with EtOAc and the organic layer washed with sat. aq NaHCO3, brine, dried (Na2SO4). and the solvent evaporated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][N:17]([CH3:21])[C:18]([N:3]1[CH:4]([CH3:8])[CH2:5][NH:6][CH2:7][CH:2]1[CH3:1])=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CC1CNCC(C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CNCC(C)N1C(=O)N(C)C
Temperature: 0 °C
Yield: 69.7 %

Procedure:
To an ice-cold solution of 2,6-dimethyl piperazine (179 mmol, 20.4 g), methylene chloride (200 mL), and triethylamine (214 mmol, 29.9 mL) was added dropwise dimethylcarbamoyl chloride (179 mmol, 16.4 mL). After 4 hr the reaction was quenched with a saturated sodium bicarbonate solution and the methylene chloride layer was collected, dried, filtered and the filtrate was evaporated to dryness to obtain an orange oil, 2,6-dimethyl-piperazine-1-carboxylic acid dimethylamide (70%, 23.1 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH:15]([CH:16]=[N:17][O:18][CH2:19][CH3:20])[CH:14]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].CCCCCC>C(Cl)Cl>[ClH:2].[CH2:19]([O:18][N:17]=[CH:16][CH:15]1[C:10]2([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH:14]1[CH2:13][NH:12][CH2:11]2)[CH3:20]
Reactant: CCON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CCON=CC1C2CNCC12c1ccc(Cl)c(Cl)c1
Yield: 153.4 %

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-((ethoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (70 mg, 0.17 mmol) obtained in step-2 of example 6 in dry DCM (5 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford a gummy solid which was titurated with hexane to afford hydrochloric acid salt of 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde O-ethyl oxime (39 mg, 95%) as a white solid as a mixture of isomers.
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34]>CN(C=O)C>[CH2:36]([N:35]([CH2:38][CH3:39])[C:33](=[O:34])[CH2:32][N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9](=[O:10])(=[O:11])[NH:8][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)[CH:13]=[CH:14][C:15]1=2)[CH3:37]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: CCN(CC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CN1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
To a flask charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIate M) (0.104 g, 0.25 mmol) was added DMF (0.7 ml), and cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (10 mg, 0.25 mmol). The mixture was stirred for 45 min at 0° C., then 30 min at room temperature. To a separate vial charged with 2-chloro-N,N-diethylacetamide (37 mg, 0.25 mmol) was added DMF (0.3 ml), then the solution of deprotonated amine. The resulting mixture was sealed and shaken at rt overnight. The mixture was quenched with the addition of MeOH, then dried under reduced pressure and purified with NH4OH modified RP-HPLC affording N,N-diethyl-2-(7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)acetamide (27.4 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01 (t, J=7.05 Hz, 3 H) 1.18 (t, J=7.10 Hz, 3 H) 3.21-3.27 (m, 2 H) 3.36 (br. s., 2 H) 3.39-3.45 (m, 2 H) 4.18 (t, J=4.35 Hz, 2 H) 4.26 (s, 2 H) 6.49 (d, J=8.71 Hz, 1 H) 6.75 (d, J=4.35 Hz, 1 H) 7.00 (d, J=2.06 Hz, 1 H) 7.13 (dd, J=8.59, 2.06 Hz, 1 H) 7.19 (d, J=4.58 Hz, 1 H) 12.47 (br. s., 1 H). m/z (ESI) 411.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([S:8][CH2:9][C@@H:10]2[O:14][CH2:13][C@@H:12]([S:15]C(=O)C)[CH2:11]2)[NH:6][C:5](=[O:19])[C:4](=[O:20])[NH:3]1.C[O-].[Na+].CO>O1CCCC1>[CH3:1][N:2]1[CH:7]([S:8][CH2:9][C@H:10]2[CH2:11][C@H:12]([SH:15])[CH2:13][O:14]2)[NH:6][C:5](=[O:19])[C:4](=[O:20])[NH:3]1
Reactant: CC(=O)S[C@@H]1CO[C@@H](CSC2NC(=O)C(=O)NN2C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN1NC(=O)C(=O)NC1SC[C@H]1C[C@H](S)CO1
Yield: 47.7 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.357 g of product from Example 84, 281 microliter of 25% sodium methoxide/methyl alcohol and 500 microliter of tetrahydrofuran to give 0.148 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([NH:32][C:19]([C:18]2[CH:17]=[N:16][N:11]3[C:12]([CH2:14][CH3:15])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-ethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.26) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 455.92 [(M+H)+]; mp 230-232° C.
Reaction SMILES: P(Br)(Br)[Br:2].[I:5][C:6]1[C:13]([I:14])=[CH:12][C:11]([I:15])=[CH:10][C:7]=1[CH2:8]O.O.C(Cl)Cl>O1CCCC1>[I:5][C:6]1[C:13]([I:14])=[CH:12][C:11]([I:15])=[CH:10][C:7]=1[CH2:8][Br:2]
Reactant: OCc1cc(I)cc(I)c1I
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: BrCc1cc(I)cc(I)c1I
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
A solution of phosphorous tribromide (3.8 ml, 40 mmol) was added dropwise to a solution of 2,3,5-triiodobenzyl alcohol 1 (9.72 g, 20 mmol) in dry tetrahydrofuran (50 ml) at 0° C. under dry nitrogen gas flow. The reaction mixture was stirred 5 minutes at 0° C., then 20 minutes at room temperature (18° C.), then cold H2O/DCM (60/60 ml) was added. The resulting aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic extracts were washed with NaHCO3aq (20 ml) and H2O (20 ml) then dried (Na2SO4), filtered and concentrated. The white solid was also washed with cold methanol (45 ml). 9.35 g of 2,3,5-triiodobenzyl bromide in the form of a white clean solid was obtained in 85% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[ClH:19]>CO>[ClH:19].[ClH:19].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Agent: Cl
Solvent: CO
Product: c1c[nH]c(C2CCNCC2)n1
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (5.5 g) in methanol was saturated with HCl and the mixture was left standing overnight. Evaporation give the product in quantitative yield. 1H NMR (400 MHz, D2O): 7.29 (s, 2H), 3.51 (br. d, J=13 Hz, 2H), 3.47-3.40 (m, 1H), 3.12 (br. t, J=13 Hz, 2H), 2.29 (br. d, J=14 Hz, 2H), 2.04-1.92 (m, 21).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccco1
Yield: 90.5 %

Procedure:
The title compound was synthesized from 4-fluoro-3-nitro-phenylamine (2.00 g, 12.81 mmol) dissolved in THF (25 ml) and Hunig's base (3.312 g, 25.62 mmol) to which was added furan-2-carbonyl chloride (1.672 g, 12.81 mmol) drop wise over 10 minutes. Reaction mixture was stirred at room temperature for 1 hr at which time water was added and the title compound was collected by filtration providing the title compound (2.90 g, 90%).
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([CH2:38][NH2:39])[CH:35]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[N:33]=1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:39][CH2:38][C:36]1[CH:35]=[C:34]([C:40]2[CH:41]=[CH:42][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:45]=2)[N:33]=[C:32]([O:31][CH3:30])[CH:37]=1)=[O:7])[CH3:2]
Reactant: COc1cc(CN)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(OC)nc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A solution of acid 4B (0.31 g, 1.1 mmol) in THF (20 mL) was added with DEPC (0.22 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27I (0.36 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1/1 EtOAc/Petroleum ether) to afford a white solid (180 mg) after crystallization from ethyl ether. Yield=30%. 1HNMR (DMSO, 200 MHz) δ 1.08 (t, 3H, J=6), 3.39 (m, 2H), 3.95 (s, 3H), 4.45 (d, 2H, J=6.2), 5.14 (s, 1H), 6.13 (s, 1H), 6.79 (s, 1H), 7.47 (t, 2H, J=8.2), 7.64 (s, 1H), 7.85 (m, 4H), 8.31 (d, 2H, J=7.8), 8.84 (bt, 1H). [M+1] 537.05 (C25H23F4N3O4S requires 537.53).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:8][C:4]1[CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1cc(Br)ccn1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Oc1ccccc1-c1ccnc(Cl)c1
Temperature: 100 °C

Procedure:
4-Bromo-2-chloropyridine (310 mg, 1.6 mmol), 531 mg (2.4 mmol) of 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol, 10.8 mg (0.016 mmol) of Pd(OAc)2, 710 mg (3.3 mmol) of K3PO4 and Xantphos[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] (18.6 mg, 0.032 mmol) in toluene: water (5:0.5 mL) were sealed in a microwave vessel and heated by microwave irradiation at 100° C. for 2 minutes. The reaction mixture was cooled and diluted with 10 mL of CH2Cl2, washed with water (5 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was dissolved in DMSO and purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 5a. LC/MS: m/z 206.1 (m+H)+, r.t (retention time)=2.86 min (10%-99% CH3CN (0.035% TFA)H2O (0.05% TFA) to give 5.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[N:9]([CH3:10])[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:7][N:6]=1.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[O:21][N:20]=1>CN(C=O)C>[Cl:30][C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:4]([CH3:3])[C:5]3[N:9]([CH3:10])[C:8]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[N:7][N:6]=3)[N:23]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CNc1nnc(-c2ccncc2)n1C
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1noc(-c2cccc(Cl)c2)n1)c1nnc(-c2ccncc2)n1C
Yield: 53.7 %

Procedure:
10 mg (0.4 mmol) NaH was added to a solution of 38 mg (0.2 mmol) methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine in 3 ml DMF under an atmosphere of nitrogen. After 10 min a solution of 50 mg (0.22 mmol) 3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole in 2 ml DMF was added. After stirring for 45 min NH4Cl(sat) was added and the mixture was extracted twice with CHCl3. The organic phase was dried and concentrated. Flashchromatography (CH2Cl2/MeOH 20:1) afforded 41 mg (54%) of the desired product. 1H NMR (CDCl3), d (ppm): 3.07 (s, 3 H) 3.71 (s, 3 H) 4.56 (s, 2 H) 7.45 (m, 1 H) 7.55 (m, 1 H) 7.62 (d, 2 H) 7.98 (d, 1 H) 8.09 (m, 1 H) 8.73 (d, 2 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=2)O1>>[CH:12]1([C:4]2[N:3]=[C:2]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(C2CCCC2)n1
Product: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Yield: 48.3 %

Procedure:
Following general procedure G, 4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.245 g, 0.98 mmol) was reacted with methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.284 g, 0.98 mmol) to afford crude product (0.179 g) as an oil. MW=378.39. 1H NMR (CDCl3, 500 MHz) δ 7.26-7.22 (m, 4H), 7.16 (s, 1H), 4.13 (s, 2H), 3.70 (s, 1H), 3.62 (s, 2H), 3.42 (quin, J=8.2 Hz, 1H), 2.15-2.07 (m, 2H), 2.00-1.80 (m, 4H), 1.76-1.65 (m, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[I:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1.[F:22][CH:23]([F:26])[CH2:24]I>CN(C=O)C>[F:22][CH:23]([F:26])[CH2:24][N:19]1[CH:20]=[CH:21][C:17]([I:16])=[N:18]1
Reactant: FC(F)CI
Reactant: Ic1cc[nH]n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: FC(F)Cn1ccc(I)n1
Reaction time: 1.25 h
Yield: 50.5 %

Procedure:
A stirred solution of NaHMDS in THF (1.0 M, 3.1 mL, 3.1 mmol) was cooled in an ice water bath under Ar. 3-iodo-1H-pyrazole (500 mg, 2.6 mmol) was added as a solution in DMF (1 mL), washing with additional DMF (2×1 mL). 1,1-difluoro-2-iodoethane (0.47 mL, 5.2 mmol) was added in one portion and the mixture was removed from the cold bath. After 1.25 h, the reaction mixture was diluted with water and EtOAc. The phases were separated, and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel (0-15% EtOAc in hexanes) to provide 1-(2,2-difluoroethyl)-3-iodo-1H-pyrazole 7.02 (339 mg). Regiochemistry was assigned by NOE studies. LCMS-ESI+ (m/z): [M+H]+ calcd for C5H6F2IN2: 259.0; found: 258.2. 1H NMR (400 MHz, Chloroform-d) δ 7.29 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.06 (tt, J=55.4, 4.3 Hz, 1H), 4.45 (td, J=13.4, 4.3 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([O:16]C)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([OH:16])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1c(Cl)c(O)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a suspension of 2-benzyl-4-chloro-5-methoxypyridazin-3(2H)-one (22.2 g, 87.47 mmol) in water (150.0 mL), potassium hydroxide (5.89 g) was added and the mixture was heated to reflux. After 3 h, the mixture was then cooled to room temperature and 6N aqueous hydrochloric acid was added and the pH of the solution was adjusted to 3.0. The precipitate was filtered, washed with water and dried under reduced pressure to give the title compound, 2-benzyl-4-chloro-5-hydroxypyridazin-3(2H)-one (20.45 g) as a white solid. HPLC: 2.40 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[O-]S(C(F)(F)[F:19])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>CO>[CH3:13][O:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[C:3]2[F:19])=[O:11]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(F)c2c1
Yield: 10.4 %

Procedure:
A solution of methyl 5-indole carboxylate (1.75 g, 10 mmol) and N-fluoro-2,4,6-trimethylpyridinium triflate (3.75 g, 13 mmol) in methanol (100 mL) was heated at reflux for 18 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel to provide 200 mg of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[CH:26][C:27]([F:32])=[C:28]([CH:31]=5)[C:29]#[N:30])=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[O:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57](B2OC(C)(C)C(C)(C)O2)[CH:56]=[N:55]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.Cl[Pd]Cl.[Fe+2].O>[F:32][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@H:10]4[O:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:57]6[CH:56]=[N:55][N:54]([CH2:53][CH2:52][O:51][CH:46]7[CH2:47][CH2:48][CH2:49][CH2:50][O:45]7)[CH:58]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)ccc1F
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(CCOC7CCCCO7)c6)cn5)CCO4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
In a pressure tube reactor, ((S)-5-(1-((4-(5-bromopyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-2-fluorobenzonitrile 50 mg (0.10 mmol) was added, and then potassium carbonate 41 mg (0.30 mmol) was added. Pd(dppf)2Cl2 4 mg (0.005 mmol) was further added, followed by 1,4-dioxane ml, 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4-(4,4,5,5-tetra methyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole 38 mg (0.12 mmol) and then H2O 0.5 ml. The mixture was stirred at room temperature for 10 minutes under nitrogen gas, and then stirred at 80° C. for 2 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Column chromatography using 60% ethyl acetate/hexane gave 2-fluoro-5-(1-(((2S)-4-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine-2-yl)-methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile 49 mg (0.08 mmol) with a yield of 80%.
Reaction SMILES: [CH:1]1(SC2C=CC(C(C3C=CC(C(F)(F)F)=C(OC)N=3)=O)=CC=2)CC1.[Si]([O:42][CH2:43][C@H:44]([CH3:60])[CH2:45][S:46]([C:49]1[N:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:52]=[N:51][N:50]=1)(=[O:48])=[O:47])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:54]1([N:53]2[C:49]([S:46]([CH2:45][CH:44]3[CH2:60][CH2:1][O:42][CH2:43]3)(=[O:47])=[O:48])=[N:50][N:51]=[N:52]2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CS(=O)(=O)c1nnnn1-c1ccccc1
Reactant: COc1nc(C(=O)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Product: O=S(=O)(CC1CCOC1)c1nnnn1-c1ccccc1

Procedure:
The title compound was obtained as a white solid (24 mg, 13% (three steps)) by performing substantially the same reaction as in Examples 1-47(1), 1-2 and 1-1(2) sequentially except for using [4-(cyclopropylsulfanyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanone obtained in Reference Example 1-68 and using 5-{[(2S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl]sulfonyl}-1-phenyl-1H-tetrazole obtained in Reference Example 3-15 in place of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[N:8]=[C:9]([O:21][CH2:22][CH3:23])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1Br.CN(C)CCN(C)C.[Cl:32]C(Cl)(Cl)C(Cl)(Cl)Cl.[NH4+].[Cl-]>C1COCC1>[Br:6][C:7]1[N:8]=[C:9]([O:21][CH2:22][CH3:23])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[Cl:32]
Reactant: CCOc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1nc(Br)c(Cl)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 86.2 %

Procedure:
n-Butyllithium (2.5M in hexanes, 3.3 mL) was added to a solution of 4,5-dibromo-2-ethoxy-1-(2-trimethylsilanylethoxymethyl)-1H-imidazole (3.0 g, 7.5 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.2 mL, 8.3 mmol) in THF (20 mL) at −78° C. After 3 minutes, a solution of hexachloroethane (2.3 g, 9.7 mmol) in THF (8 mL) was added at −78° C. The mixture was stirred at −78° C. for 1 hour and was then allowed to warm to room temperature. Saturated aq. NH4Cl (3 mL) was added and the mixture was concentrated in vacuo. The mixture was extracted with EtOAc (2×100 mL) and sat. aq. NaHCO3 (30 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography (EtOAc:hexane) afforded intermediate (26a) (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([CH2:19][CH3:20])=[C:16]([CH:18]=1)[NH2:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH2:19][CH3:20])=[C:16]([CH:18]=2)[NH2:17])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCc1ccc(Br)cc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
4-Chlorophenylboronic acid (13.2 g, 0.08 mol) and tetrakis(triphenylphosphine) palladium (0) (2.4 g, 0.002 mol) are added to a solution of 5-bromo-2-ethylaniline (14.1 g, 0.07 mol) in 1,2-dimethoxyethane (140 ml). After stirring the reaction mixture for 15 minutes at 20° C., a solution of 20% aqueous sodium carbonate (300 ml) is added to the mixture, and the resulting mixture is refluxed for 24 hours. The reaction mixture is cooled to room temperature, diluted with water and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexane to give 5-(4-chlorophenyl)-2-ethylaniline (14.3 g).