Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][OH:23])[CH:20]=2)[N:15]=[C:14]([N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[S:27](=[O:36])(=[O:35])[CH2:26][CH2:25]2)[CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[O:23])[CH:20]=2)[N:15]=[C:14]([N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[S:27](=[O:36])(=[O:35])[CH2:26][CH2:25]2)[CH:13]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl dichloride (36.3 mg, 0.29 mmol) in dichloromethane (10 mL) was added a solution of dimethyl sulphoxide (0.1 mL, 0.57 mmol) in dichloromethane (10 mL) at −78° C. dropwise. After the mixture being stirred for 10 minutes at −78° C., a solution of 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol (100 mg, 0.26 mmol, prepared in analogy to the one in Example 3-23) in dichloromethane (5 mL) was added dropwise. After the mixture being stirred for further 1 hour at −78° C., triethylamine (0.2 mL, 1.3 mmol) was. The resulting mixture was stirred at −78° C. for 1 hour and then at room temperature for further 1 hour. The reaction was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 70 mg of the product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:32]=1)[C:20](=[O:29])[CH2:21]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH2:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][N:19]([C:20](=[O:29])[CH3:21])[CH2:18][CH2:17][CH2:16][N:6]2[C:5](=[O:42])[NH:4][C:3]3[C:7]2=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=3[NH2:1])[CH:32]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CC(=O)OC(C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(C)=O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from example 20 step (i) (100 mg) was dissolved in DCM (1 ml) and TFA (0.2 ml) added. The mixture was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO3 and dried. The mixture was purified by RPHPLC, which afforded the title compound. Yield 30 mg
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:21])([CH3:20])[CH2:12][CH:13]=[C:14]2[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:22][CH2:23][CH3:24])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:21])([CH3:20])[CH2:12][CH:13]=[C:14]2[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:22][CH2:23][CH3:24])\[CH3:6])/[CH:3]=[O:4]
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CCC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-2-fluoro-3-(4,4-dimethyl-6-ethoxy-1-isopropyl-3,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-52, 0.180 g, 0.54 mmol), tetrapropylammonium perruthenate (0.027 g, 0.081 mmol) and 4-methylmorpholine N-oxide (0.158 g, 1.35 mmol) were reacted in acetonitrile (1.5 mL) and dichloromethane (7.5 mL) to give the title compound.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].IC[CH2:8][C:9]([F:12])([F:11])[F:10].[H-].[Na+]>C1COCC1>[F:10][C:9]([F:12])([F:11])[CH2:8][C:2]([CH2:8][C:9]([F:12])([F:11])[F:10])([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: FC(F)(F)CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C#N)(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Malononitril (20.15 mmol) and 1-iodo-3,3,3-trifluoropropane (42.65 mmol) were dissolved in 30 ml dry THF, and the mixture was cooled with an ice/salt bath. 1.61 g NaH (40.3 mmol) was added portionwise, keeping the temperature below 5° C. The reaction mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting with DCM, yielding 0.76 grams of an oil. 1H NMR (400 MHz, CDCl3) δ 2.62-2.49 (m, 4H), 2.31-2.24 (m, 4H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Br:12])[N:8]1[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=[C:7]1[C:6]([O:21]CC)=[N:5]2.C(O)C.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Br:12])[N:8]1[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=[C:7]1[C:6](=[O:21])[NH:5]2
Reactant: CCOC(=O)c1cn2c(n1)c(OCC)nc1cc(Br)c(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(n1)c(=O)[nH]c1cc(Br)c(Br)cc12
Yield: 60.7 %

Procedure:
A suspension of 0.1 g of the product of Step C, 10 ml of ethanol, 20 ml of water and 3 ml of 1 N sodium hydroxide solution was refluxed overnight and the resulting clear solution was acidified with concentrated hydrochloric acid. The mixture was filtered to obtain 0.053 g of 4,5-dihydro-7,8-dibromo-4-oxoimidazo-[1,2-a]-quinoxaline-2-carboxylic acid as a buff crystalline solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@H:19]1[CH2:23][CH2:22][N:21](CC2C=CC=CC=2)[CH2:20]1)=[O:17]>[OH-].[OH-].[Pd+2]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: O=C(N[C@H]1CCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1
Agent: [Pd+2]
Agent: [OH-]
Product: O=C(N[C@H]1CCNC1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 3 from (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)benzylpyrrolidin-3-yl]-2-piperidinecarboxamide [see Example 2] and 20% palladium hydroxide on carbon to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-pyrrolidin-3-yl]-2-piperidinecarboxamide as a brown foam.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[O:23]=[C:24]1[N:29]([CH2:30][C:31]([OH:33])=O)[C:28]2[CH:34]=[C:35]([O:38][C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:37][C:27]=2[O:26][CH2:25]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O>CN(C)C=O.CC#N.O>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:31](=[O:33])[CH2:30][N:29]2[C:28]3[CH:34]=[C:35]([O:38][C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:37][C:27]=3[O:26][CH2:25][C:24]2=[O:23])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CN1C(=O)COc2ccc(OC(F)(F)F)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CN(C(=O)CN1C(=O)COc2ccc(OC(F)(F)F)cc21)C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
[1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine (0.1 g, 0.34 mmol) and {3-oxo-6-[(trifluoromethyl)oxy]-2,3-dihydro-4H-1,4-benzoxazin-4-yl}acetic acid (0.108 g, 0.37 mmol) were dissolved in 1 mL of dimethylformamide. Triethylamine (0.13 mL, 0.93 mmol) was delivered to the room temperature mixture, and the solution was allowed to stir for several minutes before a separate solution of 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.164 g, 0.37 mmol) dissolved in 1 mL of dimethylformamide was added to the mixture at room temperature. The reaction was maintained at that temperature for 18 hours, before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.52 min and m/e 570 [M+1]+. The reaction mixture was filtered through a 0.45 μm PTFE Acrodisk and the crude residue was purified by prep HPLC (Waters, 50×100 mm, 84 mL/min, A: acetonitrile B: water (pH=10, NH4OH), A: 10 to 99% over 15 min, UV detection at 214 nm) to give the title compound (0.089 g. 0.16 mmol, 42%) as an off-white amorphous solid. MS (ES) m/e 570 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:7])[CH2:5][SH:6])C.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:19]Cl>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:19][S:6][CH2:5][C:4]([OH:3])=[O:7]
Reactant: ClCOc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CSCOc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of mercapto-acetic acid ethyl ester (2.4 g, 19.86 mmol) in dry DMF (20 mL) was added NaH (556 mg, 23.27 mmol, 60% in mineral oil). The mixture was stirred for 30 min. at room temperature followed by dropwise addition of 2,4-dichloro-1-chloromethoxy-benzene (3.5 g, 16.55 mmol), stirring was continued for 16 hrs at ambient temperature. The reaction was quenched by addition of water (50 mL) and extracted with diethyl ether (2×50 mL). The combined organic phases were washed with saturated aq. ammonium chloride (50 mL), dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in EtOH (20 mL) and to this solution was added aq. 32% NaOH (1 mL) and water (10 mL). Stirring was continued for 16 hrs at room temperature. The volatiles were evaporated in vacuo, water (20 mL) was added followed by washing with diethyl ether (20 mL). The aqueous phase was acidified to pH˜1 with conc. HCl followed by extraction with diethyl ether (2×25 mL). The combined organic phases were dried (Na2SO4), filtered and the solvent evaporated in vacuo affording 2.5 g (57%) of crude (2,4-dichloro-phenoxymethylsulfanyl)-acetic acid as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].I[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Cc1ccc(I)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 195 °C

Procedure:
11.2 g of 2-nitrobromobenzene are mixed with 15 g of 4-iodotoluene and the mixture is heated to 195° C. and stirred at this temperature for 3 and a half hours. After returning to room temperature, it is taken up in DCM and heated to the reflux point, the hot solution is filtered on Celite® and the DCM is then evaporated off.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:5]1[C:10](=[O:11])[N:9]([CH:23]([CH3:25])[CH3:24])[C:8]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)I
Reactant: CCCCC1Oc2cc(C(=O)OC)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a solution of 2 -butyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (9.0 g) in dimethylformamide (180 ml) were added 60% sodium hydride (in oil) (1.63 g) and 2-iodopropane (6.35 g) and the mixture was stirred at 80° C. for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:8 (v/v)] to give 2-butyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.2 g) as an oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].ClN1C(=O)CCC1=O.[Cl:19][CH2:20][C:21](=[O:46])[CH2:22][C:23]([NH:25][CH:26]1[C:44](=[O:45])[N:28]2[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]3[S:39][C:38]([CH3:40])=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12)=[O:24].P(=O)(O)(O)O.[Cl-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:19][CH2:20][C:21](=[O:46])[CH:22]([S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[C:23]([NH:25][CH:26]1[C:44](=[O:45])[N:28]2[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]3[S:39][C:38]([CH3:40])=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12)=[O:24]
Reactant: O=C(O)c1ccccc1S
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC(=O)CCl)[C@H]3SC2)s1
Agent: O=C1CCC(=O)N1Cl
Agent: O=P(O)(O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(Sc4ccccc4C(=O)O)C(=O)CCl)[C@H]3SC2)s1
Reaction time: 0.08 h

Procedure:
While a mixed solution of 0.462 g thiosalicylic acid and 0.6 g triethylamine in 8 ml of methylene chloride is cooled with ice, 0.4 g of N-chlorosuccinimide is added. The mixture is stirred for 5 minutes. Separately, a solution of 1 g 7-(4-chloro-3-oxobutyrylamino)-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and 0.6 g triethylamine in 15 ml of methylene chloride is ice-cooled and the above reaction mixture is added at one time and stirred for 2 minutes. This reaction mixture is stirred vigorously with 3 ml of 50% phosphoric acid and 7 ml of saturated aqueous sodium chloride. The organic layer is taken and the water layer is extracted with ethyl acetate. The organic layers are combined and dried. The solvent is then distilled off under reduced pressure and the residue is stirred with ether. By the above procedure is obtained 7-[4-chloro-3-oxo-2-(2-carboxyphenylthio)butyrylamino]-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid as powders. Yield 1.4 g. IR (KBr, cm-1): 1770, 1700, 1590, 1520, 1380, 1230, 750 NMR (90 MHz, d6 -DMSO, δ): 2.67(s, thiadiazole--CH3), 3.40 & 3.67(ABq, J=18 Hz, 2--CH2), 4.17 & 4.52(ABq, J=13.5 Hz, 3--CH2), 4.48(s, ClCH2CO), 5.02(d, J=4.5 Hz, 6--H), 5.58(dd, J=4.5, 9.0 Hz, 7H), 8.67(d, J=9 Hz, CONH--)
Reaction SMILES: [F:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH3:26])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([C:23](=[O:24])[NH:13][C:5]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:2]([F:1])=[CH:3][CH:4]=1)[CH3:26])([CH3:15])([CH3:16])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)c2c1NCCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCCC2
Temperature: 0 °C
Yield: 71 %

Procedure:
To an ice-cooled mixture of 6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-9-ylamine=(195 mg, 1.0826 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (225 mg, 1.19 mmol) and HOAt (147 mg, 1.083 mmol) in DCM (10 mL) was added EDCI HCl (249 mg, 1.3 mmol). The reaction mixture was stirred in the ice bath for 2 h, then diluted with DCM, washed with aqueous Na2CO3 and then water. The organic layer was dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 20-50% EtOAc in cyclohexane) affording the title compound as a pink gum (270.6 mg, 71%). LCMS (Method J): RT 3.26 min [M+H]+ 352
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1.O.[NH4+:24]>C(O)C>[CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:18]([C:19]([NH2:24])=[O:21])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNCc1cccc(-c2nc3cccc(C(=O)OC)c3o2)c1
Reactant: [NH4+]
Solvent: CCO
Solvent: O
Product: CNCc1cccc(-c2nc3cccc(C(N)=O)c3o2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Methyl 2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (80 mg, 0.27 mmol) and ammonium water (75.7 mg, 2.16 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide (16 mg, yield 21%). 1H-NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 4.29 (s, 2H), 7.48-7.52 (t, J=8 Hz, 1H), 7.70-7.74 (m, 1H), 7.81-7.83 (d, J=8 Hz, 1H), 7.90-7.98 (m, 3H), 8.34-8.43 (m, 2H), 9.06 (s, 2H); LC-MS (ESI) m/z 282 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>ClCCl.O>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: Nc1ccncc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccncc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
A mixture of 4-aminopyridine (10 g, 106 mmol) and pivaloyl chloride (12.9 g, 107 mmol) in 200 mL dichloromethane was cooled to 0° C. and treated slowly with triethylamine (10.9 g, 108 mmol), warmed to room temperature, stirred overnight, and diluted with water. The aqueous layer was extracted three times with dichloromethane and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The product was recrystallized from toluene to provide the desired product (14 g, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=[CH:3][C:2]([O:1][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.2 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (1.5 g, 3.5 mmol), methyl bromoacetate (0.92 g, 6.0 mmol), potassium carbonate (0.55 g, 4.0 mmol) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography to give methyl {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetate (1.9 g, yield 94%) as pale-yellow crystals.
Reaction SMILES: CN(C)CCN(C)C.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][C:41](/[CH:44]=[CH:45]/[C:46]([N:48]2[C@H:52]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@H:51]([CH3:59])[N:50]([CH3:60])[C:49]2=[O:61])=[O:47])=[CH:40][CH:39]=1)(=[O:37])=[O:36]>C1COCC1.[Cu]I>[CH3:34][S:35]([C:38]1[CH:39]=[CH:40][C:41]([C@H:44]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:45][C:46]([N:48]2[C@H:52]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@H:51]([CH3:59])[N:50]([CH3:60])[C:49]2=[O:61])=[O:47])=[CH:42][CH:43]=1)(=[O:36])=[O:37]
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)/C=C/c2ccc(S(C)(=O)=O)cc2)C(=O)N1C
Reactant: Br[Mg]c1ccccc1
Agent: [Cu]I
Agent: CCCC[B+]CCCC
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2ccccc2)N(C(=O)C[C@@H](c2ccccc2)c2ccc(S(C)(=O)=O)cc2)C(=O)N1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of copper (I) iodide (960 mg, 5.0 mmol) and THF (20 mL) was added N,N,N′,N′-tetramethylethylenediamine (0.83 mL, 5.5 mmol) and the resulting mixture was stirred at room temperature for 10 min. then cooled to −78° C. Phenylmagnesium bromide (5.0 mL, 1M in THF, 5.0 mmol) was added and the resulting mixture stirred at −78° C. for 15 min. A solution of di-n-butylboron triflate (3.0 mL, 1M in diethyl ether, 3.0 mmol) and (E)-(4S,5R)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-one (Method D, 1.0 g, 2.51 mmol) in THF (15 mL) was added and the resulting mixture was stirred whilst allowing to warm to room temperature for 18 h. The reaction mixture was washed with saturated aqueous ammonium chloride, water and brine, dried (MgSO4) and evaporated. The residue was purified by eluting through a 20 g Bond Elut with gradient of isohexane to ethyl acetate giving the sub-titled compound (1.49 g, 100%); NMR (CDCl3): 0.78 (d, 3H), 2.82 (s, 3H), 3.00 (s, 3H), 3.78 (dd, 1H), 3.80 (m, 1H), 3.98 (dd, 1H), 4.72 (m, 1H), 5.19 (d, 1H), 6.99 (m, 2H), 7.22 (m, 8H), 7.48 (d, 2H), 7.79 (d, 2H); MS: 477 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].N.S(=O)(=O)(O)[OH:17]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:14])=[O:17]
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Reactant: O=S(=O)(O)O
Agent: N
Product: NC(=O)c1cnn(-c2ccccc2)c1N
Temperature: 0 °C

Procedure:
9 g of 5-amino-1-phenyl-4-pyrazolecarbonitrile were stirred at 10°-15° C. with 40 ml of concentrated sulphuric acid until all of the solid had dissolved. The mixture was poured on to 150 g of crushed ice and made basic with concentrated ammonia solution. The precipitated product was filtered off and purified by chromatography on silica gel using 5% methanol in ethyl acetate for the elution. There were obtained 5.8 g of 5-amino-1-phenyl-4-pyrazolecarboxamide. A sample recrystallized from water melted at 163°-165° C.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:22]2[NH:31][C:25]3=[N:26][CH:27]=[C:28]([F:30])[CH:29]=[C:24]3[CH:23]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:22]2[NH:31][C:25]3=[N:26][CH:27]=[C:28]([F:30])[CH:29]=[C:24]3[CH:23]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOCCS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 50 °C
Yield: 92.6 %

Procedure:
A mixture of 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-vinyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.68 mmol) and 10% palladium on activated carbon (90 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% dichloromethane/ethyl acetate) afforded 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-ethyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (280 mg, 93%): LC/MS m/e calcd for C24H29FN2O3S [M+H]+ 445.57, observed 445.1.