Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:14])[CH2:10][C:11](=[O:13])[N:29]1[CH2:28][CH2:27][CH2:26][CH2:24]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: C[C@H](CC(=O)N1CCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-butyric acid (150 mg, 0.74 mmol) and HATU (309 mg, 0.81 mmol) in DMF (2 mL) was added pyrrolidine (0.19 mL, 2.21 mmol). The resultant yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated to afford ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-carbamic acid tert-butyl ester as a colorless oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[N:17]=1)[C:12](O)=[O:13].[O-:24][N+:25]1[C:30]([C:31]([F:34])([F:33])F)=[CH:29][CH:28]=[C:27]([C@H:35]([NH2:37])[CH3:36])[CH:26]=1.[CH2:38](Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:34][C:31]([C:30]1[N+:25]([O-:24])=[CH:26][C:27]([C@H:35]([NH:37][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([CH:18]([OH:23])[C:19]([F:22])([F:20])[F:21])[N:17]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:10]=2)[CH3:36])=[CH:28][CH:29]=1)([F:33])[CH3:38]
Reactant: ClCCCl
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)nc(C(O)C(F)(F)F)c1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1cc(-c2ccc(F)cc2F)nc(C(O)C(F)(F)F)c1)c1ccc(C(C)(F)F)[n+]([O-])c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-6-(2,2,2-trifluoro-1-hydroxyethyl)isonicotinic acid (0.15 g, 0.45 mmol) in DMF (2.5 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (0.16 g, 0.59 mmol), EDC (0.17 g, 0.90 mmol), HOAT (61.3 mg, 0.45 mmol) and triethylamine (0.38 mL, 2.7 mmol). The mixture was stirred at 60° C. After 1 h, the mixture was cooled to ambient temperature and saturated aqueous NaHCO3 was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The mixture was suspended in dichloromethane and the solid was filtered. The solid cake was washed with cold dichloromethane and dried under hi-vac. The product was treated with HCl (2.0 M in ether) to give the hydrochloride salt of the title compound (0.18 g). HRMS 522.1063 (M+1). 1H NMR (400 MHz, CD3OD): δ 8.48 (s, 1H); 8.17 (s, 1H); 8.09-7.99 (m, 2H); 7.89 (d, J=8.4 Hz, 1H); 7.65 (d, J=8.4 Hz, 1H); 7.10 (t, J=9.1 Hz, 2H); 5.28-5.18 (m, 2H); 1.62 (d, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3([C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[N:20]=[CH:19][CH:18]=[CH:17]5)[CH2:13][CH2:12]3)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>O1CCOCC1.CCOC(C)=O.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>[N:20]1[C:21]2[C:16](=[CH:15][C:14]([C:11]3([C:8]4[N:6]5[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]5=[N:10][N:9]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-cyclopropyl]-quinoline (30 mg, 0.093 mmol), PdCl2(PPh3)2 (6.5 mg, 0.0093 mmol) and tributyl(1-ethoxyvinyl)stannane (67 mg, 0.186 mmol) in 3 mL of 1,4-dioxane was heated at 90° C. for 3 h under nitrogen. The reaction mixture was diluted with EtOAc, washed with aqueous KF. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl, and the solution was stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.89 (dd, 1H), 8.13-8.04 (m, 3H), 7.93 (d, 1H), 7.87 (dd, 1H), 7.70 (d, 1H), 7.40 (dd, 1H), 2.51 (s, 3H), 1.92-1.89 (m, 2H), 1.73-1.69 (m, 2H). LCMS (method A): [MH]+=330, tR=4.18 min.
Reaction SMILES: ClC1C=C(C=CC=1Cl)CN1CCOC(CN)C1.FC(F)(F)C([NH:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][NH:26][CH2:25]1)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36]Br>>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][N:26]1[CH2:27][CH2:28][O:29][CH:24]([CH2:23][NH2:22])[CH2:25]1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Reactant: Fc1ccc(CBr)cc1F
Agent: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: NCC1CN(Cc2ccc(F)c(F)c2)CCO1

Procedure:
Intermediate 20 was prepared in an analogous manner to Intermediate 1 (Alternative Procedure) from Intermediate 19 and 3,4-difluorobenzyl bromide, followed by deprotection to yield the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.O.[NH2:32][NH2:33].O>CN(C=O)C>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (304 mg, 0.76 mmol, prepared in Synthetic Example 18) in DMF (7.5 ml) was added hydrazine monohydrate (80%, 108 μl, 2.70 mmol, 3.6 eq.), and the mixture was then stirred at 100 to 110° C. for 5 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (260 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([CH:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].C=O.O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([CH:27]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28]3)([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: OC(c1cccnc1)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)C1CCCNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CN1CCCC(C(O)(c2cccnc2)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)C1
Reaction time: 8 h

Procedure:
To a mixture of (2,4-dichloro-3-phenylquinolin-6-yl)(piperidin-3-yl)pyridin-3-ylmethanol•TFA (15 mg, 0.022 mmol, Example 93), 37% formaldehyde in water (0.010 mL, 0.13 mmol) and MeOH (1 mL) was added NaBH3CN (4.0 mg, 0.064 mmol). The mixture was stirred overnight and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4) δ 8.95 (s, 1H), 8.54-8.68 (m, 2H), 8.41 (d, J=7.58 Hz, 1H), 7.96-8.13 (m, 2H), 7.72 (dd, J=5.14, 7.58 Hz, 1H), 7.53 (d, J=7.09 Hz, 3H), 7.33 (d, J=6.85 Hz, 2H), 3.48-3.64 (m, 1H), 3.10-3.21 (m, 1H), 2.96-3.10 (m, 1H), 2.83-2.97 (m, 1H), 2.80 (s, 3H), 2.66 (s, 1H), 2.01-2.13 (m, 1H), 1.82-2.01 (m, 1H), 1.54-1.82 (m, 2H); MS m/e 478.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:10][CH2:11][CH3:12])[CH2:4][C:5]([O:7]CC)=O.[OH:13][CH2:14][C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].CCN(CC)CC>CCO.C1COCC1>[OH:13][CH2:14][CH:15]([CH2:21][N:1]1[CH2:2][CH:3]([CH2:10][CH2:11][CH3:12])[CH2:4][C:5]1=[O:7])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=C(CO)C(=O)OCC
Reactant: CCCC(CN)CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC1CC(=O)N(CC(CO)C(=O)OCC)C1
Reaction time: 6 h
Yield: 37.8 %

Procedure:
In a three neck flask, fitted with a reflux condenser, under argon, a solution of ethyl 3-(aminomethyl)hexanoate (11.8 g, 0.042 mol) in EtOH (50 ml) is added via a pump-syringe (5 ml/h) onto a solution of ethyl 2-(hydroxymethyl)acrylate x278 (5 g, 0.038 mol) and Et3N (8.03 ml) in THF (100 ml) at room temperature. After 6 h, the reaction mixture is filtered on celite, washed with saturated NaHCO3 and the aqueous layer is extracted with CH2Cl2 (2×150 ml), dried with MgSO4, filtered and concentrated in vacuo. The crude reaction mixture is purified by chromatography on silicagel (CH2Cl2/MTBE/MeOH 50/49/1), to afford 3.7 g of ethyl 3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoate c279.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=O.[N:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:13]=1)=[C:10]=[O:11]>>[OH:7][CH2:6][C:2]1([CH3:8])[NH:1][C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21]([F:22])([F:23])[F:24])[CH:13]=2)[C:3]1=[O:5]
Reactant: CC(N)(CO)C(=O)O
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Product: CC1(CO)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O

Procedure:
Follow the procedure in Example 12, using 2-amino-3-hydroxy-2-methyl-propionic acid and 4-isocyanato-1-nitro-2-trifluoromethyl-benzene, known from the literature as starting material to yield the title compounds as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[Br-:1].[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: OCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 72 h

Procedure:
An equivalent of 5-bromopentanol and an equivalent of triphenylphosphine in refluxed ethanol are placed in a flask. After 72 hours of agitation in these conditions, and once returned to ambient temperature, the ethanol is evaporated under vacuum and the residue is placed into toluene at 4° C. overnight. The (5-hydroxypentyl)triphenylphosphonium bromide formed is filtered on a frit, rinsed with methyl tert-butyl ether then dried under vacuum.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:17][CH:18]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[CH2:19][CH2:20][CH3:21])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:17][CH:18]([O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])[CH2:19][CH2:20][CH3:21])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)OC(CCC)OC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC(=O)OC(CCC)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl butanoate (700 mg, 2.3 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 35 (210 mg, 27% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.95 (m, 8H), 1.22-1.41 (br. m, 5H), 1.56 (m, 2H), 1.68-1.73 (m, 4H), 1.89-1.92 (m, 2H), 2.13 (tt, J=12, 3.2 Hz, 1H), 2.30 (t, J=7.2 Hz, 2H), 6.65 (t, J=5.6 Hz, 1H), 7.45 (t, J=6.0 Hz, 1H), 12.04 (s, 1H). MS (ESI) m/z 366.21 (M+Na)+; 342.16 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>C(O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)cc3)oc2C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
Ethyl 3-[{[4-({1-[5-(4-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (660 mg) which is a synthetic intermediate in Example 151 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 13.5 min were collected, and concentrated. The obtained amorphous compound (319 mg) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), 1N lithium hydroxide (1.3 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (288 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]3=[O:17])=[CH:6][N:5]2[C:18]=1[CH3:19].[Cl:20][C:21]1[S:25][CH:24]=[C:23]([CH2:26]O)[CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:20][C:21]1[S:25][CH:24]=[C:23]([CH2:26][O:16][C:13]2[CH:14]=[CH:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]4[N:5]([C:18]([CH3:19])=[C:2]([CH3:1])[N:3]=4)[CH:6]=3)[C:11](=[O:17])[CH:12]=2)[CH:22]=1
Reactant: Cc1nc2ccc(-n3ccc(O)cc3=O)cn2c1C
Reactant: OCc1csc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cn2c1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To a solution of 1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (174 mg) and tributylphosphine (358 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (447 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (90 mg) as a white solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl:7][C:8]1[C:13]([CH2:14]Cl)=[CH:12][N:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C(#N)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:16]([F:19])([F:17])[F:18])[N:11]=[CH:12][C:13]=1[CH2:14][C:5]#[N:6]
Reactant: FC(F)(F)c1cc(Cl)c(CCl)cn1
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CCc1cnc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
Trimethylsilylcyanid (TMSCN) (69.3 g, 0.7 mol) was added to a solution of 4-chloro-5-(chloromethyl)-2-(trifluoromethyl)pyridine (Int-13) (80 g, 0.348 mol) and Tetra-n-butylammoniumfluoride (129.5 g, 0.7 mol) in acetonitrile (1.5 L) slowly. Then the mixture was stirred at 20-30° C. for 2 hours. Thin layer chromatography (petroleum ether: EtOAc=3:1) showed all of starting material was consumed. The mixture was concentrated and the residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc=20:1˜3:1 to yield [4-chloro-6-(trifluoromethyl)pyridin-3-yl]acetonitrile (Int-14) (50 g, 60% from NMR, 39% of yield) as yellow syrup.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10].[OH-].[Na+]>CO>[C:22]([NH:21][CH2:20][CH2:19][CH2:18][N:5]([C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10])[CH2:4][C:3]([OH:29])=[O:2])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: COC(=O)CN(CCCNC(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(CC(=O)N(CCCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O

Procedure:
N-(N′-Boc-3′-aminopropyl)-N-[(1-thyminyl)acetyl]glycine methyl ester (3.02 g, 0.00732 mol) was dissolved in methanol (25 ml) and stirred for 1.5 h with 2 M sodium hydroxide (25 ml). The methanol was removed by evaporation, in vacuo, and pH adjusted to 2 with 4 M hydrochloric acid at 0° C. The product was isolated as white crystals by filtration, washed with water (3×10 ml), and dried over sicapent, in vacuo. Yield 2.19 g (75%). Anal. for C17H26N4O7, H2O. found (calc.) C, 49.95 (49.03); H, 6.47 (6.29); N, 13.43 (13.45). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][NH:18][C:17]3=[O:21])[N:8]=2)=[CH:4][CH:3]=1.C([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)C.[C:33](=O)([O-])[O-:34].[Na+].[Na+]>COCCOC>[CH3:33][O:34][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][NH:18][C:17]4=[O:21])[N:8]=3)=[CH:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C1NCCN1CCNc1nccc(-c2ccc(Br)s2)n1
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc(-c3ccnc(NCCN4CCNC4=O)n3)s2)cc1
Temperature: 150 °C

Procedure:
A mixture of 1-(2-(4-(5-bromothiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazolidin-2-one (30 mg, 0.08 mmol), 4-ethylphenylboronic acid (16 mg, 0.1 mmol), tetrakis(triphenyl-phosphine)palladium (9 mg, 0.008 mmol) and 2 M sodium carbonate (0.08 mL, 0.16 mmol) in 1,2-dimethoxyethane (3 mL) was heated at 150° C. for 25 min in a Personal Chemistry microwave reactor. Upon cooling, the mixture was filtered through celite and washed with ethyl acetate. Solvent was removed under vacuum and the product was purified by column chromatography eluting with MeOH/CH2Cl2 (1:20) to yield a slight yellow solid (18, mg, 56%). MS (M+H)+ 396.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N#Cc1ccc(N)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
14.83 g of N-(tert-butoxycarbonyl)glycine was dissolved in 50 ml of tetrahydrofuran, and 13.73 g of 1,1'-carbonylbis-1 H-imidazole was gradually added thereto and stirred at room temperature for 3 hours. 10 g of p-aminobenzonitrile was added thereto and stirred for 3 hours. Then, the solvent was removed by distillation under a reduced pressure. Water was added to the resulting residue, and the crystals thus formed were taken out by filtration, washed with a small amount of ethanol and then dried under a reduced pressure. Thus was obtained 20.5 g of 2-(tert-butoxycarbonylamino)-N-(4-cyanophenyl)acetamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:21])[O:3]1.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[Br:28][C:11]1[C:6]2[NH:5][C:4](=[O:21])[O:3][C:2]([CH3:22])([CH3:1])[C:7]=2[CH:8]=[C:9]([C:12]2[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=2)[C:15]#[N:16])[CH:10]=1
Reactant: BrBr
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)OC(=O)Nc2c(Br)cc(-c3cc(F)cc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
To a mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile (0.5 g, 1.7 mmol) and sodium acetate (0.2 g, 2.4 mmol) in acetic acid (5 mL) was added, at room temperature under nitrogen, bromine (0.12 mL, 2.34 mmol). The reaction mixture was stirred for 20 hours and then poured into ice water (30 mL). The precipitate was collected on a filter and washed with water (3×5 mL) to yield 3-(8-bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as an off-white solid (0.48 g, 75%): mp 216-217° C.; 1H-NMR (DMSO-d6) δ 9.78 (s, 1H), 8.18 (t, 1H, J=1.6 Hz), 8.02-8.08 (m, 2H), 7.81 (m, 1H), 7.75 (d, 1H, J=1.8 Hz), 1.66 (s, 6H). MS (ESI) m/z 373, 375 [M−H]−.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)(C)[CH3:12].ICC>C1COCC1>[CH2:11]([C:5]1[O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH3:12]
Reactant: c1ccc2occc2c1
Reactant: [Li]C(C)(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2ccccc2o1

Procedure:
2-Ethylbenzo[b]furan was prepared by the method of example 40A with benzo[b]furan (7.3 mmols), 0.86 g) t-BuLi (1.7 m, 9.4 mmols) iodoethane (4 mmols, 0.9 mls) and THF (15 ml). 1.0 g (95%) of a yellow liquid was isolated.
Reaction SMILES: FC(F)(F)C(O[C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.CN([CH:28]=[O:29])C.[CH3:30][OH:31]>>[N:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([C:30]([O:29][CH3:28])=[O:31])[CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CO
Reactant: CN(C)C=O
Reactant: O=C(Oc1ccc2cccnc2c1)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2cccnc2c1
Temperature: 60 °C

Procedure:
To a stirred solution of quinolin-7-yl trifluoroacetate (750 mg, 2.7 mmol), PdCl2(Ph3P) (95 mg, 0.14 mmol), and triethylamine (1.2 mL, 8.4 mmol) in 1:2 DMF/MeOH (39 mL) was degassed and sparged with CO, and the mixture was heated at 60° C. for 48 h. The mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was diluted with a 5% solution of LiCl, and washed with CHCl3 (3×250 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 3:1 ethyl acetate/hexanes) provided methyl quinoline-7-carboxylate (185 mg): ESI MS m/z 188 [M+H]+.