Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:19][CH:20]([F:24])[C:21](O)=O>C1(C)C=CC=CC=1>[F:19][CH:20]([F:24])[C:21]1[NH:1][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:10][C:11]=2[N:12]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Reactant: O=C(O)C(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)F)[nH]c12
Temperature: 25 °C

Procedure:
A mixture of methyl 2,3-diamino-5-morpholinobenzoate (40.16 g, 160 mmol) and 2,2-difluoroacetic acid (46.08 g, 480 mmol) in toluene (500 mL) was stirred at reflux temperature for 15 h. Then the mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was purified by silica gel chromatography eluted with petroleum ether:EtOAc=2:1 to afford the desired product. Then, it was dissolved with EtOAc (2 L) and washed with aqueous NaHCO3 (1 L) and brine (1 L). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the desired product (40.9 g, 82%) as a yellow solid. 1H NMR showed this compound is in a form of tautomeric mixture (major tautomer/minor tautomer=5/1) 1H NMR of the major tautomer (300 MHz, DMSO-d6): δ ppm 3.14 (t, 4H, J=4.8 Hz), 3.78 (t, 4H, J=4.8 Hz), 3.96 (s, 3H), 7.21 (t, 1H, J=52.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.65 (d, 1H, J=2.4 Hz), 12.92 (s, 1H); LC-MS: m/e=312 [M+1]+
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=3[F:31])[CH:13]=2)[CH:9]=[N:8]1.Cl>C1COCC1>[F:31][C:23]1[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=[CH:27][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([CH2:6][CH:2]=[O:1])[CH:11]=3)[S:20][C:19]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cnn(CC5OCCO5)c4)sc23)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 145 (900 mg, 2.034 mmol) in THF (20 mL) was added 3M HCl (30 mL) and the reaction mixture was heated to reflux for 24 hours. The mixture was cooled to RT, and concentrated. The residual aqueous solution was treated with solid sodium bicarbonate and then extracted with DCM. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The crude aldehyde 146 (810 mg, 100% yield) was used in the next step with no additional purification. MS (m/z)=399.3 (M+H)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]=[CH:12]2)=[CH:7][N:6]=1)(=[O:4])=[O:3].[Cl:22]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.O1CCCC1>[Cl:22][C:14]1[N:13]=[CH:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][CH:7]=2)[C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(-n2cncc2-c2ccccc2)cn1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2cnc(Cl)c2-c2ccccc2)cn1
Yield: 60.7 %

Procedure:
2-(methylsulfonyl)-5-(5-phenyl-1H-imidazol-1-yl)pyridine (83 mg, 0.28 mmol), N-chlorosuccinimide (39 mg, 0.29 mmol), azobisisobutyronitrile (2 mg) and tetrahydrofuran (10 mL) were added into a 25 mL round bottom flask, and stirred to conduct reflux reaction for 18 hours. After the reaction, the solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to yield white solid target compound (56 mg, 0.17 mmol). 1H-NMR (300 MHz, CDCl3): δ 3.26 (3H, s), 7.19-7.22 (2H, m), 7.38-7.40 (3H, m), 7.66 (1H, dd), 7.71 (1H, s), 8.11 (1H, dd), 8.58 (1H, dd); LC-MS m/z: 335 [M++1]; purity (HPLC)>95%.
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.[CH:15](=O)[CH2:16][CH3:17]>O>[CH:15]([N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[N:4][N+:1]([O-:3])=[O:2])=[CH:16][CH3:17]
Reactant: CCC=O
Reactant: O=[N+]([O-])N=C1NCCN1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC=CN1CCNC1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
A mixture comprising 4.0 g of 2-nitroiminoimidazolidine, 20 ml of 1,3-dimethyl-2imidazolidine, 7.5 g of phosphorus oxychloride and 2.7 g of propionaldehyde was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated. The crystals thus precipitated out were sludged with ethyl acetate, filtrated and dried to give 1.7 g of 1-(1-propenyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=[N:3]1.F[P-](F)(F)(F)(F)F.[PH4+].CCN(C(C)C)C(C)C.[NH2:36][C@@H:37]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:60])([F:59])[F:58])[CH2:38][N:39]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]1=[O:49]>C(Cl)Cl>[O:48]=[C:47]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:49])[N:39]1[CH2:38][C@@H:37]([NH:36][C:16]([C:9]1[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:18])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:59])([F:58])[F:60]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C(F)(F)F
Reaction time: 2 h
Yield: 93.6 %

Procedure:
At room temperature, a mixture of 4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylic acid (235 mg, 80% purity, 0.68 mmol), phosphoniumhexafluorophosphate (PyBrOP) (381 mg, 0.19 mmol), DIPEA (0.59 mL, 3.4 mmol) and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (261 mg, 0.75 mmol) in DCM (5 mL) was stirred for 2 h. The reaction solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (386 mg, 86%) as a white solid: LC-MS (ES) 607 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:33])[CH3:32]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:28][N:33]=[C:31]([CH3:32])[N:30]=3)[CH2:10]2)=[O:8])[CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 55 mg (0.75 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 15 mg (6% of theory).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9].[OH-].[K+]>ClCCl>[NH2:27][CH2:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][CH:18]([C:14]2[CH:13]=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=2)[CH2:19][CH2:20]1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.1 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl N-(3-{4-[3-(acetylamino)phenyl]piperidino}propyl)carbamate (340 mg) in dry dichloromethane (10 mL) and stirred at room temperature for 5 h. A 10% aqueous solution of KOH was added to the reaction mixture until pH>6 and then the dichloromethane was removed in vacuo. The aqueous layer was frozen and lyophilized to give a solid, which was extracted with methanol. Removal of the solvent gave the desired product (120 mg) as an oil: 1H NMR (CDCl3) δ 7.23-7.16 (apparent t, 1H, J=7.5 Hz), 6.95-6.92 (m, 1H), 3.03-2.99 (m, 2H), 2.77-2.73 (t, 2H, J=6.6 Hz), 2.50-1.60 (m, 10H), 2.13 (s, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH3:11][C:12]1[C:21]([C:22](OCC)=[O:23])=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[N:14]2[N:13]=1>C1C=CC=CC=1>[CH3:11][C:12]1[C:21]([C:22]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:23])=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[N:14]2[N:13]=1
Reactant: CCOC(=O)c1c(C)nn2c(C)cccc12
Reactant: OC1CN2CCC1CC2
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1nn2c(C)cccc2c1C(=O)OC1CN2CCC1CC2
Reaction time: 3 h
Yield: 21.7 %

Procedure:
After a suspension of 350 mg (2.76 mmol) of 3-quinuclidinol in 30 ml of benzene was refluxed for 1.0 hours by using a Dean-Stark apparatus, 0.1 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 3 hours. Unreacted sodium was removed and 200 mg (0.92 mmol) of ethyl 2,7-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 60 mg (0.20 mmol) of the title compound were obtained as white crystals (yield: 22%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:4]=2[C:5]([O:8]C)=[N:6][CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[Br:1][C:2]1[C:3]2[N:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Br)c2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCCC3)c3c(Br)c[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of 4-(7-bromo-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (60.0 mg) in acetonitrile (10 mL) were added sodium iodide (40.0 mg) and chloro(trimethyl)silane (0.135 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (35.2 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1C
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1C
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 37-4 (640 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (470 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:4]([C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])=[C:3]([O:2][CH3:1])[CH:19]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)NCc1ccc(C)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N)ccc1C(=O)NCc1ccc(C)nc1

Procedure:
A solution of 2-methoxy-N-(6-methylpyridin-3-yl)methyl-4-nitrobenzamide (448 mg, 1.49 mmol) in EtOH and EtOAc (8 mL each) is stirred and ammonium formate (375 mg, 6 mmol) and 10% Pd/C (100 mg) are added. The mixture is heated at reflux for 20 min, cooled, filtered through celite, the solid is washed with EtOH and the combined solvents are evaporated to afford the title compound.
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].[CH2:18]([SH: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:20][CH2:18][CH3:19])=[N:7][C:8]=2[CH:15]=1
Reactant: Cn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSCC(C)(O)c1nc2cc(Cl)c(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol (141 mg) in MeOH (4 mL) at room temperature was added a solution of ethanethiol (34 mg) and sodium methoxide (0.132 mls of 25 wt % in MeOH). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:8][C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([N:8]([N:3]1[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]1[CH3:1])[C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:13][CH:14]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)n1Nc1ccc(N2CCOCC2)nn1
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc(N2CCOCC2)nn1)n1c(C)ccc1C
Temperature: 110 °C

Procedure:
A mixture of 6 g (22 m mol) of N-(2,5-dimethyl-1H-pyrrol-yl)-6-morpholino-3-pyridazineamine, 30 ml of acetic anhydride, and 6 ml of pyridine is heated for one hour at 110° C. The reaction mixture is evaporated to dryness under vacuum and the oily residue is dissolved in 150 ml of ethyl acetate. The organic solution is washed first with 50 ml of an aqueous solution of sodium bicarbonate and then with 50 ml of water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].Cl.[CH3:24][C:25]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26]1>CS(C)=O.CC(OC)(C)C.CCOC(C)=O.Cl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:27]1[CH2:28][CH2:29][C:25]([OH:30])([CH3:24])[CH2:26]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: CC1(O)CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC1(O)CCN(c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.264 mmol), 3-methylpyrrolidine-3-ol hydrochloride (72.8 mg, 0.529 mmol), and TEA (147 μL, 1.058 mmol) in DMSO (199 μL) was stirred at 90° C. for 16 h. Additional TEA (73.7 μL, 0.529 mmol) was added to the mixture and stirring was continued for 72 h at 100° C. The cooled RM was diluted with TBME/EtOAc (1:1)(30 mL), sequentially washed 0.5 M HCl (3×5 mL), brine (5 mL) and then evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 20% to 60% EtOAc-EtOH+0.1% NH4OH (9:1)) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.98 min, m/z=459/461.0 [M+H]+, m/z=457/459 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 3H) 1.77-1.95 (m, 2H) 3.32-3.35 (m, 1H) 3.37-3.48 (m, 1H) 3.65 (d, J=10.03 Hz, 1H) 3.75 (td, J=9.41, 7.09 Hz, 1H) 4.79 (s, 1H) 6.90 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.81-7.91 (m, 3H) 8.13 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][Sn](C)(C)C>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.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: C[Sn](C)(C)C
Reactant: Cc1cc(Br)c2nccn2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)c2nccn2c1

Procedure:
Microwave a mixture of 6-methyl-8-bromoimidazo[1,2-a]pyridine (1.0 g, 4.76 mmol), tetramethyl tin (2.0 g, 11.2 mmol), and palladium tetrakis(triphenylphosphine) (0.28 g, 0.024 mmol) at 120° C. for 10 minutes at 300 watts. Subject the reaction mixture to flash silica gel chromatography to provide a quantitative yield of the title compound as a tan oil.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][C@H:65]1[CH2:70][CH2:69][C@H:68]([OH:71])[CH2:67][CH2:66]1>C(Cl)Cl>[CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:8]([NH:64][C@H:65]2[CH2:70][CH2:69][C@H:68]([OH:71])[CH2:67][CH2:66]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N[C@H]2CC[C@H](O)CC2)C2CCCCC2)c(OC)n1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid (300 mg, 0.70 mmol, 1.0 equiv) in DCM (5 mL) was added triethylamine (142.1 mg, 194.7 μL, 1.39 mmol, 2.0 equiv) and HATU (341.6 mg, 0.90 mmol, 1.3 equiv) and the mixture stirred at 40° C. After 15 min, trans-4-amino-cyclohexanol hydrochloride (137.04 mg, 0.90 mmol, 1.3 equiv; [CAS RN 50910-54-8]) was added and stirring continued at 50° C. for 2 h. Removal of the solvent mixture under reduced pressure and purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate yielded 0.33 g (90%) of the title compound. MS (ES+): 529 (M+H).
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@H:4]1[C:15]([NH2:17])=[O:16])#[N:2]>CO>[NH2:2][CH2:1][C@@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@@H:4]1[C:15]([NH2:17])=[O:16]
Reactant: N#C[C@H]1CN(Cc2ccccc2)C[C@H]1C(N)=O
Solvent: CO
Product: NC[C@@H]1CN(Cc2ccccc2)C[C@@H]1C(N)=O
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Dissolve (3S,4R)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxamide (1.50 g, 6.55 mmol) in methanol (10 mL). Add NiCl 6H O (3.11 g, 13.1 mmol) followed by NaBH (0.99 g, 26.2 mmol) portionwise. The reaction was stirred for 2 hours, but it was not complete. Additional NaBH (0.5 g) was added and the reaction stirred another 1 hour. The solution was filtered through a plug of celite and washed with methanol. The solvent was evaporated under reduced pressure yielding a crude oil (1.51 g). LCMS: m/z 234.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.Cl[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([O:22][C:25]5[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Reactant: Cc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)nn1
Yield: 83.4 %

Procedure:
A stirred solution of Example 57 (0.05 g, 0.15 mmol) and 3-chloro-6-methylpyridazine (0.019 g, 0.15 mmol) in DIPEA (0.1 mL, 0.3 mmol) was heated to 180° C. under microwave irradiation in a sealed tube for 4 h, then concentrated in vacuo. Purification by preparative HPLC (Method 7) gave the title compound (0.053 g, 19%) as an off-white solid. δH (CDCl3) 7.98 (1H, d, J 2.4 Hz), 7.34 (1H, d, J 9.0 Hz), 7.08 (1H, d, J 9.0 Hz), 7.00-6.80 (2H, m), 5.45 (1H, s), 4.40-4.30 (2H, m), 4.20-4.10 (2H, m), 2.86 (2H, s), 2.64 (3H, s), 1.38 (6H, s). LCMS (ES+) 424.0 (M+H)+, RT 2.92 minutes (Method 2).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:14]([OH:17])[C:15]#[CH:16].C(NC(C)C)(C)C>C(#N)C.[Cu]I>[N:7]1([CH2:6][C:5]2[CH:12]=[CH:13][C:2]([C:16]#[C:15][CH2:14][OH:17])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Brc1ccc(CN2CCCC2)cc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: OCC#Cc1ccc(CN2CCCC2)cc1
Temperature: 60 °C

Procedure:
A mixture of 4.8 g (20.0 mmol) 1-(4-bromo-benzyl)-pyrrolidine, 1.75 mL (30.0 mmol) propargylalcohol, 2.31 g (2.0 mmol) tetrakis-triphenylphosphane-palladium, 381 mg (2.0 mmol) CuI and 7.07 mL diisopropylamine in 100 mL acetonitrile is heated for 14 h at 60° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>O1CCCC1.[Br-].C([N+](CC)(CC)CC)C>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: BrCCCCBr
Reactant: O=C1CCCN1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCN1CCCCBr
Yield: 38.8 %

Procedure:
To a suspension of 37 g of powdered KOH in 500 ml of tetrahydrofuran (THF) were added 25.2 g of tetraethylammonium bromide. Then, a solution of 51.6 g of 2-pyrrolidinone and 129.6 g of 1,4-dibromobutane in 100 ml of THF was added dropwise to the mixture. The mixture was heated and refluxed for 2 hours. The precipitate was filtered, and the THF evaporated. The residue was dissolved in dichloromethane, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue distilled to yield 51.2 g of 1-(4-bromobutyl)-2-pyrrolidinone (38.8% yield) having a boiling point of 120° C. at 0.05 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Br:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Br:25])[CH:27]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc(Br)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(Br)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 56.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-bromophenol (45 mg, 0.26 mmol) to give the title compound (38 mg, 56%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).