Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9]C)=[O:8])[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([NH2:22])=[O:21]>CN(C=O)C>[NH2:22][C:20](=[O:21])[CH2:19][O:11][C:3]1[C:2]([Br:1])=[CH:6][S:5][C:4]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1scc(Br)c1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)COc1c(Br)csc1C(=O)O
Temperature: 85 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (53.0 g), potassium carbonate (46.2 g), 2-bromoacetamide (37.0 g) and DMF (500 ml) was stirred at 60° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water (300 ml) was added to the residue, and the solid was collected by filtration. To the obtained solid were added potassium carbonate (61.6 g), water (20 ml) and MeOH (500 ml, and the mixture was stirred at 85° C. for 1 hr. After cooling to room temperature, the solid were collected by filtration. The obtained solid was dissolved in water (300 mL), and the mixture was adjusted with 6 N hydrochloric acid to pH 3. The obtained solid was collected by filtration, and washed with water to give the title compound (50.5 g, 80.8%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1C(=O)C=[N+]=[N-].CCN(CC)CC.C[CH2:22][O:23][C:24]([CH3:26])=[O:25]>C1COCC1.CO.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:26][C:24]([O:23][CH3:22])=[O:25]
Reactant: Cc1ccc(C(=O)C=[N+]=[N-])c(Br)c1
Reactant: CCOC(C)=O
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-bromo-4-methylphenyl)-2-diazoethanone (A83) (667 mg, 2.79 mmol) in THF (4.3 mL) and MeOH (4.3 mL) was added a solution of silver benzoate (96 mg, 0.42 mmol) in Et3N (1.13 mL, 11.2 mmol). The resulting mixture was stirred for 2 hours at room temperature then passed through a plug of silica gel eluting with 50% EtOAc in petroleum benzine 40-60° C. The eluent was evaporated in vacuo and the residue was adsorbed onto silica gel and separated using silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A84 as a clear oil (678 mg, >99%); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=0.7 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.07 (dd, J=7.7, 1.0 Hz, 1H), 3.76 (s, 2H), 3.70 (s, 3H), 2.30 (s, 3H). LCMS-A: rt 6.070 min.
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:8]=2[N:7]=1)([OH:5])[CH3:4].[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)(=[O:20])[CH3:19].C[O-].[Na+]>CO>[Cl:16][C:14]1[C:13]([Cl:17])=[CH:12][C:9]2[N:10]([CH3:11])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:28][C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:27][CH:26]=3)=[N:7][C:8]=2[CH:15]=1
Reactant: Cn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(SCC(C)(O)c2nc3cc(Cl)c(Cl)cc3n2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol (60 mg) in MeOH (2 mL) at room temperature was added a solution of 4-acetamidothiophenol (40 mg) and sodium methoxide (0.047 mls of 25 wt % in MeOH). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The crude product was purified by flash chromatography (25%-100% EtOAc/hexanes) to yield the title compound as a white foam solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[C:25]1([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2CC2CCCCC2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A mixture of 3-bromo-1-cyclohexylmethyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.25 mmol), PhSnBu3 (0.1 mL, 0.30 mmol), and PdCl2(PPh3)2 (36 mg, 0.051 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., water and EtOAc were added. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5% EtOAc/CH2Cl2) to give 71 mg of the title compound. MS: (+) m/z 393.37 (M+1).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:8]([O:25]C)[C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@@:14]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:15]([NH:17][OH:18])=[O:16])[CH:11]=1>C(Cl)Cl>[F:5][C:6]1[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:8]([OH:25])[C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@@:14]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:15]([NH:17][OH:18])=[O:16])[CH:11]=1
Reactant: COc1c(-c2ccccc2)c(F)cn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@@](CCn1cc(F)c(-c2ccccc2)c(O)c1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
Boron tribromide (760 μL, 0.76 mmol, 1.0 M in dichloromethane) was added to a solution of (2R)-4-(5-fluoro-3-methoxy-2-oxo-4-phenylpyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (156 mg, 0.378 mmol) in DCM (16.0 mL) at 0° C. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated to afford a brown solid. The crude product was purified via prepratory HPLC to afford the title compound as a yellow solid (25.4 mg, 16.9%). MS (LCMS) m/z 399.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (s, 3H) 2.11-2.25 (m, 1H) 3.07 (s, 1H) 3.13 (s, 2H) 3.70-3.88 (m, 1H) 4.02-4.26 (m, 1H) 7.11 (d, J=7.81 Hz, 1H) 7.37-7.65 (m, 5H).
Reaction SMILES: C(O)C.[C:4]([N:8]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11](Cl)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1>C(N(CC)CC)C>[C:4]([N:8]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11]([NH:27][CH2:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)c1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: NCc1ccncc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccncc2)cnn(C(C)(C)C)c1=O

Procedure:
7 ml of an absolute ethanol solution of 170 mg of 2-tert-butyl-5-chloro-4-methoxycarbonylpyridazin-3-(2H)-one, 76 mg of 4-picolylamine and 80 mg of triethylamine, was reacted for 4 hours under heating and refluxing and then left to cool. Ethanol was distilled off under reduced pressure, and 0.3 g of the obtained oil was subjected to column chromatography. Using an eluent (ethyl acetate:methanol=20:1), 0.13 g of the desired product (Compound No. 22) having a melting point of from 99° to 100° C., was obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[CH:5]([C:6](=[O:23])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH2:4]1.[OH-].[K+].[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])=[O:32])([CH3:29])([CH3:28])[CH3:27].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][C:37]([NH:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[CH:5]([C:6](=[O:23])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH2:4]1)=[O:38])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: C[C@]12CC[C@H](N)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC(=O)N[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
A solution of 3β-aminoandrostane-6,17-dione hydrochloride (150 mg) in CH2Cl2 was treated with powdered KOH (25 mg) and stirred for 15 min. 4-(tert-Butoxycarbonylamino)butyric acid (98 mg), EDAC (168 mg) and 4-dimethylaminopyridine (8 mg) were added at 0° C. The reaction temperature was raised to room temperature and stirred for 24 hrs. The mixture was washed with water (2×10 mL) and 5% NaHCO3 (10 mL). The organic layer was dried and evaporated to dryness. The residue was purified by flash chromatography (SiO2; CH2Cl2:MeOH:NH3 9:1:0.1) to give 3β-[4-(tert-butoxycarbonylamino)butyramido]-androstane-6,17-dione (161 mg, 75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.68 (1H, d), 6.77 (1H, t), 3.46 (1H, m), 2.87 (2H, m), 2.45-1.10 (24H, m), 1.36 (9H, s), 0.78 (3H, s), 0.66 (3H, s).
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH:52]([CH3:98])[CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:79])([F:78])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:93])([O:90]CC)[O:87][CH2:88][CH3:89])=[CH:83][C:82]=4[O:96][CH3:97])[N:71]=3)=[CH:61][CH:60]=2)[CH:56]=[N:55]1>>[OH:50][CH2:51][CH:52]([CH3:98])[CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:79])([F:77])[F:78])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:90])([OH:93])[O:87][CH2:88][CH3:89])=[CH:83][C:82]=4[O:96][CH3:97])[N:71]=3)=[CH:61][CH:60]=2)[CH:56]=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)CO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)CO)c4)nc3C(=O)NC)n2)c(OC)c1

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 18B): 1H NMR (CD3OD, 400 MHz): δ=9.02 (br. s., 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.64 (br. s., 1H), 7.12 (s, 1H), 6.98-6.92 (m, 1H), 4.29 (dd, J=6.7, 13.5 Hz, 1H), 4.08 (dd, J=7.1, 13.6 Hz, 1H), 3.92-3.83 (m, 5H), 3.48 (d, J=5.8 Hz, 2H), 3.03 (d, J=21.0 Hz, 2H), 2.99 (s, 3H), 2.33-2.23 (m, 1H), 1.15 (t, J=7.1 Hz, 3H), 0.95 (d, J=7.1 Hz, 3H). MS (ESI): m/z=679.75 [M+H]+. UPLC: tR=1.16 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(F)cc4)c3c2)cc1

Procedure:
The title compound, white solid (40 mg, 31%), MS (ISP) m/z=373.1 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (92.0 mg, 447 μmol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.C(O)(=O)C.[N:14]([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:9]=[N:14][NH:8][C:5]2=[CH:6][N:7]=1
Reactant: Cc1cc(Br)ncc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc2cn[nH]c2cn1
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
To a solution of 6-bromo-4-methylpyridin-3-amine (7.76 g, 0.0415 mol) in acetic acid (412.8 mL, 7.260 mol) was added Sodium nitrite (2.87 g, 0.0416 mol) in 4.0 ml water (Bioorg. Med. Chem. 15 (2007) 2441-2452). The reaction was stirred for 15 min and allowed to stand at room temperature (rt) for 2 days (d). The reaction was concentrated and diluted EtOAc then washed with NaHCO3 and brine. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by chromatography (DCM/MeOH) eluted at 5% MeOH) to give 5-bromo-1H-pyrazolo[3,4-c]pyridine (79.1% yield)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[OH:25][CH2:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:25][CH2:26][CH2:27][CH2:28][NH:29][C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]2[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:7])[CH:14]=2)=[CH:20][CH:19]=1)=[O:23]
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCO)cc1
Yield: 83.5 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (30 mg, 0.093 mmol), 3-hydroxypropylamine (7 mg, 0.093 mmol), HATU (35.5 mg, 0.093 mmol), HOBT (12.6 mg, 0.093 mmol) and DIPEA (48 μl, 0.28 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-(4′-{[(3-hydroxypropyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide (29.4 mg, 83%). NMR; δH [2H6]—DMSO 9.91,(1H, s), 8.50,(1H, t), 8.35,(1H, s), 7.90,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.97,(1H, m), 4.49,(1H, t), 3.47,(2H, q), 3.33,(2H, m), 2.19,(3H, s), 1.69,(2H, m). LCMS: retention time 2.77 min, MH+379.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:13]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)=[CH:11][CH:10]=3)=[O:16])[CH2:14][CH2:15]1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccncc4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with pyridin-4-ylboronic acid (25 mg, 0.200 mmol) to afford the crude product (50 mg) as an off-white solid: ESI MS m/z 487 [C29H34N4O3+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][N:16]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[N:15]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.CN(C=O)C.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][N:16]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:20]4)[N:15]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)n3)n2)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(CC(F)(F)F)C4)n3)n2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
2-(3-(3-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 130; 13.0 mg, 0.0301 mmol) was suspended in DMF (301 μL, 0.0301 mmol) and treated with diisopropylethylamine (31.4 μL, 0.180 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.07 mg, 0.0391 mmol). The reaction mixture was stirred at ambient temperature for 15 hours. Another portion of 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.0 mg, 0.87 mmol) was added and stirred for another 24 hours. The reaction mixture was then purified by reverse phase HPLC using 0-100% acetonitrile/water gradient, followed by preparative TLC using 10% MeOH/EtOAc to afford 2-(3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile (9.6 mg, 72% yield). MS (apci) m/z=442.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:9]([CH2:12][S:13]([N:16]2[CH2:21]C[CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Na+].BrC1C=CC(CS([O-])(=O)=[O:34])=C(C(OC)=O)C=1OC.N1CCC(O)C1>>[Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:9]([CH2:12][S:13]([N:16]2[CH2:17][CH2:18][CH:19]([OH:34])[CH2:21]2)(=[O:14])=[O:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)[O-])ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCCCC2)ccc(Br)c1OC
Agent: OC1CCNC1
Agent: [Na+]
Product: COC(=O)c1c(CS(=O)(=O)N2CCC(O)C2)ccc(Br)c1OC

Procedure:
Prepared as a colourless oil by proceeding in a similar manner to Intermediate 147, starting from methyl (4-bromo-3-methoxy-2-methoxycarbonylphenyl)methanesulphonic acid sodium salt (Intermediate 148, 0.134 g) and 3-pyrrolidinol (0.12 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:15]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[O:30]1[CH2:35][CH2:34][N:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1>>[CH3:16][C:15]1[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:13]=[CH:12][C:11]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([N:39]2[CH2:40][CH2:41][CH:36]([N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH2:37][CH2:38]2)=[C:3]([N+:27]([O-:29])=[O:28])[CH:4]=1)=[O:10]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1c(C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c([N+](=O)[O-])c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 9.1 %

Procedure:
The reaction and treatment in the same manner as in Example 162 using N-(4-chloro-3-nitrophenyl)-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide (1.0 g) and 4-morpholinopiperidine (1.4 g), the title compound (0.12 g) was obtained, melting point: 225–230° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].CNCCNC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCOCC1.[Cu]I>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCCCN1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCCCC2=O)c(C)c1

Procedure:
Prepared analogously to Example 31a from methyl 4-bromo-3-methyl-benzoate and piperidin-2-one in the presence of copper(I)iodide, N,N′-dimethyl-ethylenediamine and potassium carbonate in toluene and dioxane under an argon atmosphere.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.ClC[C:18]1[CH:23]=[CH:22][C:21]([O:24]C2C=CC=CC=2)=[CH:20][CH:19]=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[O:24]([C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][CH:2]=1)[CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1cccc(Oc2ccccc2)c1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 1-chloromethyl-4-phenoxybenzene (21.5 g), a 2M ethanolic solution of sodium ethylate (50 cc) and ethyl 2-mercaptoacetate (12.2 g) in ethanol (200 cc). Ethyl (3-phenoxybenzylthio)acetate (28.8 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[CH2:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CN2CCCc3ccccc32)cc1
Reaction time: 3 h

Procedure:
1,2,3,4-tetrahydroquinoline (2.66 g, 0.02 mol), benzaldehyde (3.12 g, 0.03 mol) and glacial acetic acid (0.67 ml, 0.012 mol) were dissolved in methanol (10 ml). Sodium cyanoborohydride (0.675 g, 0.0107 mol) was added portionwise, controlling the resulting vigorous gas evolution by the rate of addition. After 3 hours, the reaction mixture was poured into 50 ml 1N HCl and extracted 3×40 ml ether. The organic layers were combined, dried (MgSO4) and stripped to yield crude title product contaminated with benzyl alcohol. The crude product was dissolved in 50 ml ether, cooled to 0° C. and diffused with HCl gas until precipitation of hydrochloride salt was complete. The ether was decanted from the resulting semi-solid salt. The salt was washed with 20 ml fresh ether, the ether decanted, and the washed salt taken up in 50 ml of fresh ether and 50 ml of H2O. The pH was adjusted to 12 with 1N NaOH, and the ether layer separated, dried (K2CO3) and stripped to 2.47 g of product still containing some residual benzyl alcohol. Repeated conversion to hydrochloride salt and back to free base gave purified title product, 2.02 g.