Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][NH:22][CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][N:22]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)nn1C
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)CC#N)CC4C3)n2)nn1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a solution of 5-chloro-N2-(1,5-dimethyl-1H-pyrazol-3-yl)-N4-(octahydro cyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (522.0 mg, 1.50 mmol) and 2-cyanoacetic acid (127.6 mg, 1.50 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added HATU (690.2 mg, 1.82 mmol) and Et3N (313.5 mg, 3.10 mmol). After addition, the reaction mixture was stirred at rt for 1.5 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=80/1) to give the title compound as a beige solid (455.2 mg, 73.1%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.I[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:30][C:31]([CH3:34])([CH3:33])[CH2:32][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)C)c2ncnn12
Temperature: 90 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-iodo-2,2-dimethylpropane (0.36 mL), cesium carbonate (0.89 g) and N,N-dimethylacetamide (10 mL) was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.4 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH2:31])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([C:35]1[C:36]([N:41]=[CH:42][N:43]([CH3:45])C)=[N:37][CH:38]=[CH:39][CH:40]=1)#N>>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:45]2[C:35]3[CH:40]=[CH:39][CH:38]=[N:37][C:36]=3[N:41]=[CH:42][N:43]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2N)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2Nc2ncnc3ncccc23)cc1
Yield: 24 %

Procedure:
The product of Example 64A was reacted with the product of Example 29A using the procedure of Example 13D substituting the product of Example 64A for the product of Example 13C and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title compound (31 mg, 24%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.48 (s, 9 H) 7.01 (d, J=8.46 Hz, 1 H) 7.32 (m, 4 H) 7.54 (d, J=8.46 Hz, 2 H) 7.71 (m, 2 H) 7.82 (d, J=7.72 Hz, 1 H) 8.01 (s, 1 H) 8.08 (s, 1 H) 8.64 (s, 1 H) 8.96 (d, J=8.09 Hz, 1 H) 9.11 (d, J=2.94 Hz, 1 H) 9.61 (s, 1 H) 10.35 (s, 1 H) 10.36 (s, 1 H); MS (ESI+) m/z 643/645 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:7](=[O:15])[CH2:6][CH2:5]2.[N-:16]=[N+]=[N-].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:7](=[O:15])[NH:16][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(Cl)c(C(F)(F)F)cc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2cc(Cl)c(C(F)(F)F)cc21
Yield: 54.8 %

Procedure:
5-Chloro-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (I-85d: 600 mg, 2.5575 mmol) in TFA (25 mL) was reacted with sodium azide (549 mg, 8.439 mmol) for 5 hours at 80° C. Purification by column chromatography on silica gel (1% methanol in CHCl3), afforded 350 mg of the product (54.8% yield).
Reaction SMILES: FC1C=CC([NH:8][C:9]([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)=[O:10])=CC=1.C([N:19](CC)CC)C>C1COCC1>[C:11]1([C:14]([NH2:19])=[O:15])([C:9]([NH2:8])=[O:10])[CH2:13][CH2:12]1
Reactant: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl chloride prepared via the procedure in Example 47 (0.13 g, 0.538 mmol), Example A9 (0.123 g, 0.414 mmol), and triethylamine (0.065 ml, 0.621 mmol) were dissolved in THF (3 ml). The mixture was stirred at RT for 30 min, filtered to remove triethylamine HCl, concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM) to obtain N-(2-fluoro-5-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.067 g, 32% yield). MS (ESI) m/z: 504.2 (M+H+).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=[O:2].[Br:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][N+:17]([CH3:26])=[CH:18]2.C([O-])([O-])=O.[Na+].[Na+].OO>C(Cl)Cl>[Br:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]([CH3:26])[C:18]2=[O:2]
Reactant: C[n+]1ccc2c(Br)ccc([N+](=O)[O-])c2c1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ccc2c(Br)ccc([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of 5-bromo-2-methyl-8-nitroisoquinolinium tosylate (20.0 g) in CH2Cl2 (400 mL) was added aq. Na2CO3 (5%, 400 mL) and hydrogen peroxide (30%, 20 mL). The resulting mixture was stirred at room temperature for 16 h, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (5×100 mL). The combined organic layer was washed with water (100 mL), dried over sodium sulfate and evaporated to give the crude product, which was purified by column chromatography on silica gel (EtOAc/CH2Cl2 (1:9)) to give 2.2 g of the desired product (yield: 8%). 1H NMR (CDCl3, 300 MHz): δ=3.60 (s, 3H), 6.90 (d, J=7.8 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.30 (d, J=7.2 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:30][CH2:29]1.[C:43]([O:47][C:48]([NH:50][CH2:51][C@H:52]([C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=1)[C:53](O)=[O:54])=[O:49])([CH3:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(=O)OCC>[Cl:62][C:59]1[CH:60]=[CH:61][C:56]([C@H:52]([C:53]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[CH2:29][CH2:30][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:54])[CH2:51][NH:50][C:48](=[O:49])[O:47][C:43]([CH3:46])([CH3:44])[CH3:45])=[CH:57][CH:58]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
HBTU (0.033 g, 0.086 mmol) was added to a solution of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.025 g, 0.086 mmol), (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.026 g, 0.086 mmol), and DIEA (0.045 mL, 0.26 mmol) in DCM (1.2 mL). The reaction mixture was stirred at room temperature for 90 minutes. 2M Na2CO3 was added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 12S (ca. 100 mL; 4:1 DCM:EA flushed to elute DIEA, then 1:9 DCM:EA eluted product) to give tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.043 g, 100% yield) as a yellow residue. LC/MS (APCI+) m/z 500.1 [M+H]+; Rf: 2.68.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[CH2:15][CH2:16][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[CH2:26]([NH:30][C:2]1[N:3]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:21][CH2:20][CH:19]([CH2:25][CH2:24]3)[CH2:18]2)[N:5]=[C:6]([N:8]2[CH2:14][CH:13]3[CH2:12][CH2:11][CH:10]([CH2:16][CH2:15]3)[CH2:9]2)[N:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: Clc1nc(N2CC3CCC(CC3)C2)nc(N2CC3CCC(CC3)C2)n1
Reactant: CCCCN
Product: CCCCNc1nc(N2CC3CCC(CC3)C2)nc(N2CC3CCC(CC3)C2)n1

Procedure:
Nine grams (0.025 mole) of 3,3'-(6-chloro-s-triazine-2,4-diyl)bis-3-azabicyclo[3.2.2]nonane and 9.7 g. (0.13 mole) n-butylamine is placed in a glass liner in a bomb and then heated in an oil bath maintained at 160°-180° C. for 16 hours. After cooling, the contents of the bomb are rinsed with chloroform and water into a flask and 50 ml. of 10 N NaOH is added. The solution is then evaporated in vacuo and the aqueous solution remaining is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered through Magnesol® and the Magnesol® washed with chloroform. Removal of solvent in vacuo, column chromatography on silica gel and recrystallization of the pure fractions containing the major component from n-heptane gives 4.9 g. of colorless prisms, m.p. 101°-103° C.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH2:3][CH:4]([C:8]([O-:10])=[O:9])[CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O>[N:13]([C@H:7]1[CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:9])[CH2:3][C@@H:2]1[OH:1])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C([O-])C1CCC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 70 °C
Reaction time: 24 h
Yield: 121.2 %

Procedure:
Benzyl (1R*,3S*, 4R*)-3,4-epoxycyclohexane-1-carboxylate (52.3 g) was dissolved in N,N-dimethylformamide (1000 ml), ammonium chloride (21.9 g) and sodium azide (18.1 g) were added, and the mixture was heated to 70° C. and stirred for 24 hours. The solvent was distilled off under reduced pressure, and water was added to conduct extraction with ethyl acetate. The resultant organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (61.8 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([NH:11][NH:12][CH:13]=O)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CN(C=O)C>[N:11]1[N:12]=[CH:13][N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:9]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=CNNC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Oc1ccc(-n2cnnc2)cc1

Procedure:
4-aminophenol (1 g, 9.16 mmol) and bisformyl hydrazine (888 mg, 10.08 mmol) were dissolved in a mixture of toluene (30 mL) and DMF (3 mL), followed by addition of pTSA (1.92 g, 10.08 mmol). The mixture was heated under reflux for 3 hours. Upon cooling, the mixture separated to two layers. The upper toluene layer was discarded. The lower dark DMF layer was directly purified by column chromatography using a 115 gram biotage silica gel cartridge eluting with 20-40 ethyl acetate/hexanes (gradient) to give the product as pale yellow solid. LRMS tale: 161.1; obs: 162.4 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]1[C:17](=[O:18])[N:16]2[C@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21][CH2:22][N:15]2[C:14](=[O:30])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([NH:10][C@@H:11]1[C:17](=[O:18])[N:16]2[C@H:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:20][CH2:21][CH2:22][N:15]2[C:14](=[O:30])[CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of benzoyl chloride (1.61 g, 11.47 mmol) in CH2Cl2 (15 ml) was added dropwise to a stirred ice cold mixture of (1S,9S) t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 3.1 g, 10.43 mmol), dry CH2Cl2 (20 ml) and diisopropylethylamine (4.54 ml, 26.06 mmol). The mixture was kept cold for 1 h then left at room temperature for 0.5 h. The mixture was diluted with CH2Cl2, washed twice with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (0-5% methanol in CH2Cl2) to afford 211e (4.0 g, 95%) of a colourless glass: mp 74-76° C.; [α]D30 −75.0° (c 0.12, CH2Cl2). IR (KBr) 3350, 2979, 2938, 1736, 1677, 1662, 1536, 1422, 1276, 1250, 1155; 1H NMR (CDCl3) δ8.72 (2H, m), 7.53-7.40 (3H, m), 7.07 (1H, d, J=7.2), 5.30 (1H, dd, J=3.0, 5.8), 5.12 (1H, m), 4.66 (1H, m), 3.51 (1H, m), 2.90 (2H, m), 2.38 (1H, dd, J=13.2, 6.8), 2.25 (1H, m), 1.9 (2H, m), 1.70 (1H, m). Anal. Calcd for C21H27N3O50.5H2O: C, 61.45; H, 6.88; N, 10.24. Found C, 61.69; H, 6.71; N, 10.18.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([NH:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:11][S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)(=[O:22])=[O:21])[C:5]([NH:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCNc1ncc(Br)cc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: CCNc1ncc(Br)cc1NS(=O)(=O)c1ccc(OC)cc1
Yield: 34.8 %

Procedure:
5-Bromo-N2-ethylpyridine-2,3-diamine (290 mg, 1.34 mmol, purchased from Aurora Building Blocks reference A01.414.067) was treated with 4-methoxybenzene-1-sulfonyl chloride (280 mg, 1.35 mmol) according to the method described in Preparation 15b to give 180 mg (35% yield) of the title compound as an oil. Purity 99%.
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([CH2:36][OH:37])=[CH:26][C:27]=1[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([CH2:36][O:37][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:26][C:27]=1[NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[O:22]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1sc(CO)cc1NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1sc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyldiphenylchlorosilane (1.7 g) dissolved in dichloromethane (5 mL) was added dropwise over the course of 10 min to a mixture of 3-tert-butoxycarbonylamino-5-hydroxymethylthiophene-2-carboxylic acid methyl ester (1.4 g), 4-dimethylaminopyridine (30.2 mg), N,N-diisopropylethylamine (1.3 mL) in dichloromethane (30 mL). The reaction mixture was then stirred at room temperature for 6 h. The mixture was mixed with dichloromethane and saturated ammonium chloride solution. The organic phase was washed with water, dried over sodium sulfate and concentrated. The product with the molecular weight of 525.74 (C28H35NO5SSi) was obtained in this way; MS (ESI): 426 (M-Boc+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[C:23]([F:25])[F:24])=[CH:18][CH:17]=1)C1C=CC=CC=1.B(Br)(Br)Br.C(Cl)Cl.CSC.B(F)(F)F.C(Cl)Cl.CSC.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:24][C:23]([F:25])=[CH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[CH:17][CH:18]=1
Reactant: FC(F)=Cc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: BrB(Br)Br
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CSC
Product: Oc1ccccc1Cc1ccc(C=C(F)F)cc1
Reaction time: 0.03 h
Yield: 89.7 %

Procedure:
In a nitrogen stream, a solution of 1-benzyloxy-2-[4-(2,2-Difluorovinyl)benzyl]benzene (984.5 mg, 2.93 mmol) in methylene chloride (12 mL) was cooled to −78° C., and a boron tribromide-dimethylsulfide methylene chloride solution (1.0 M, 7.32 mL) was added dropwise thereto. The reaction mixture was stirred at the same temperature for two minutes and under cooling with ice for two hours, and furthermore the boron trifluoride-dimethylsulfide methylene chloride solution (4.39 mL) was added dropwise thereto. The reaction mixture was stirred at the same temperature for 3.5 hours, then a sodium hydroxide aqueous solution and a saturated sodium hydrogencarbonate aqueous solution was added thereto and the mixture was extracted with methylene chloride, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:7)] to obtain the title compound (647.5 mg, 90%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[CH3:16])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:15]([CH3:16])=[C:6]([NH2:5])[N:7]=2)[CH:10]=1
Reactant: Cc1c(NC(=O)C(F)(F)F)nc2ccc(F)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(N)nc2ccc(F)cn12
Temperature: 100 °C

Procedure:
2,2,2-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)acetamide (0.188 g, 0.00072 mol) was dissolved in methanol (4.0 mL) and water (0.5 mL). Potassium carbonate (0.40 g, 0.0029 mol) was added and heated in the microwave for 45 min at 100° C. The solvent concentrated and residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried (magnesium sulfate) then chromatographed on silica (55:40:5, DCM:acetonitrle:MeOH) to give 6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine Rf 0.47, (55:40:5, DCM:acetonitrle:MeOH); MS m/z 166 (M+H).
Reaction SMILES: CO[C:3](=O)[CH:4]([N+:13]([O-:15])=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=C.Cl>C(O)(C)(C)C.C(OCC)C>[CH3:22][O:21][C:17](=[O:20])[CH2:6][CH:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:4]([N+:13]([O-:15])=[O:14])[CH2:3][CH2:18][C:17]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(C(C)c1ccccc1)[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 356 g of nitro-3-phenylbutanoic acid methyl ester, 138 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-phenylheptanedioic acid dimethyl ester.
Reaction SMILES: Cl.[C:2]([N:6]([C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH3:7])(=[O:5])[CH:3]=[CH2:4].[C:20]([N:28]1[CH2:33][CH2:32][CH2:31][C:30]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)([CH2:34][CH2:35][CH2:36]OS(C)(=O)=O)[CH2:29]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[ClH:48].[C:2]([N:6]([C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][N:11]([CH2:36][CH2:35][CH2:34][C:30]2([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=3)[CH2:31][CH2:32][CH2:33][N:28]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:29]2)[CH2:12][CH2:13]1)[CH3:7])(=[O:5])[CH:3]=[CH2:4]
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Reactant: C=CC(=O)N(C)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)N(C)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 80 °C
Yield: 63.8 %

Procedure:
A mixture of 0.27 g of 4-(acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride, 0.45 g of the compound obtained in step B of EXAMPLE 1 and 0.3 g of K2CO3 in 3 ml of DMF is heated at 80° C. for 2 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a gradient of a DCM/MeOH mixture (99/1; v/v to 95/5; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.2 g of the expected product, m.p.=128° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][N:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:7]([C:8]([NH:34][CH2:33][C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[N:32][CH:31]=2)=[O:9])=[CH:6][C:5]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)O)c2C)cc1
Reactant: Cc1ncc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)NCc3cnc(C)nc3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with 2,4′-dimethyl-5-(pyrrolidin-1-ylsulfonyl)biphenyl-3-carboxylic acid (40 mg, 0.11 mmol), (2-methylpyrimidin-5-yl)methanamine (18 mg, 0.15 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (106 mg, 0.28 mmol), N,N-diisopropylethylamine (39 μL, 0.22 mmol) and N,N-dimethylformamide (1.33 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to afford the compound as a white solid.