Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:22][CH:21]=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:22][CH:21]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCc1ccccc1)c1ccc(O)cc1O
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(N=C(CCc3ccccc3)c3ccc(O)cc3O)cc2)=NN1
Temperature: 190 °C

Procedure:
A mixture containing 1.45 g of 1-(2,4-dihydroxyphenyl)3-phenyl-propan-1-one and 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one was heated for 72 h at 190° C. The product was treated with ethyl acetate, yield 0.37 g (16%), m.p. 208°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH:36]([OH:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:42][CH:36]([CH3:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCCC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(C)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 33.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-heptanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was, then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (25 mg, yield 31%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:46]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH2:60])[C:57]([OH:59])=[O:58])=[CH:51][C:50]=1[NH2:61])(=[O:48])[CH3:47]>CN(C=O)C>[C:46]([C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH:60][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:57]([OH:59])=[O:58])=[CH:51][C:50]=1[NH2:61])(=[O:48])[CH3:47]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccc(CC(N)C(=O)O)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)cc1N
Reaction time: 0.5 h

Procedure:
To 4-nitrobenzoic acid (50.1 mg), HATU (114 mg) and DIEA (105 μL) was added 1 mL DMF and the mixture was stirred for 30 minutes. Then the resulting solution was added to 3-(4-acetyl-3-aminophenyl)-2-aminopropanoic acid (66.7 mg, 1.0 equiv) in 1.0 mL DMF, and the reaction was stirred at room temperature, monitored by LC-MS. The title product was then isolated by preparative HPLC. 1H NMR (400 MHz, MeOD): δ 8.28 (d, J=8.8 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 7.72 (d, J=8.4 Hz, 1H), 6.69 (d, J=1.6 Hz, 1H), 6.61 (dd, J′=8.4 Hz, J″=1.6 Hz, 1H), 3.28 (dd, J′=13.8 Hz, J″=10.0 Hz, 1H), 3.02 (dd, J′=13.8 Hz, J″=10.0 Hz, 1H), 2.51 (s, 3H); ESI-MS (m/z) 372.34 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](OC)=O)=[CH:4][CH:3]=1.[Na].[N+]([O-])(O)=O.[NH2:21][NH:22][C:23]([NH2:25])=[NH:24]>CO>[NH2:25][C:23]1[N:24]=[C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:21][N:22]=1
Reactant: N=C(N)NN
Reactant: COC(=O)c1ccc(Cl)c2ccccc12
Agent: [Na]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: Nc1n[nH]c(-c2ccc(Cl)c3ccccc23)n1

Procedure:
The synthesis method of Example 7-(2) was applied. The compound (1.90 g) obtained in (3) above, methanol (20 ml), metallic sodium (810 mg) and aminoguanidine nitrate (4.8 g) were used as reagents to give a brown solid (2.27 g). The obtained compound was used as it was in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:11]=[C:10]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Br:25])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: OB(O)c1ccccc1Br
Reactant: Nc1nc(N2CCOCC2)c2nc(Cl)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(N2CCOCC2)c2nc(-c3ccccc3Br)ccc2n1
Yield: 25.9 %

Procedure:
A solution of 2-amino-4-morpholino-6-chloro-pyrido[3,2-d]pyrimidine (265 mg, 1 mmol), potassium carbonate (690 mg, 5 mmol), tetrakis(triphenylphosphine)palladium(0) (100 mg) in dioxane (10 ml) and water (3 ml) was refluxed. To this refluxing solution was added dropwise (with a speed of 0.25 ml/min) a solution of 2-bromo-phenyl boronic acid (220 mg, 1.1 mmol) in dioxane (2 ml). Once the addition was complete, the reaction mixture was refluxed for another 2 hours. The reaction mixture was cooled down and the solvents were evaporated in vacuo. The residue was redissolved in dichloromethane and extracted with water. The combined organic layers were dried over Na2SO4 and the crude residue was purified by preparative TLC on silica, using a methanol/dichloromethane mixture in a ratio of 10:90 as mobile phase, yielding the pure title compound (100 mg, yield: 30%) which was characterised as follows: MS (m/z): 386, 388 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[C:4]([CH3:12])[N:3]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:12])[C:5]([C:6]2[O:7][C:13](=[O:14])[NH:9][N:8]=2)=[CH:10][CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(Cl)ccc1C(=O)NN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)ccc1-c1n[nH]c(=O)o1
Temperature: 25 °C

Procedure:
6-Chloro-2-methylnicotinohydrazide (60 mg, 0.32 mmol) and 1,1′-carbonylbis(1H-imidazole) (58 mg, 0.36 mmol) were taken up in dimethylformamide (1.6 ml). The reaction was heated overnight to 60° C. It was then allowed to cool to room temperature, taken up in ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([CH2:11][O:12]S(C)(=O)=O)[S:10][C:6]=2[CH:5]=1.[Cl-].[NH4+:20]>CN(C)C=O>[F:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([CH2:11][O:12][C:4]3[CH:18]=[CH:17][C:7]([NH:20][C:11](=[O:12])[CH3:9])=[CH:6][CH:5]=3)[S:10][C:6]=2[CH:5]=1
Reactant: CS(=O)(=O)OCc1nc2ccc(F)cc2s1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2nc3ccc(F)cc3s2)cc1
Reaction time: 0.05 h
Yield: 28 %

Procedure:
18.8 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 64.6 mg of4-acetamidophenol in 1.3 ml of dimethylformamide cooled in an ice-water bath, and the resulting mixture stirred at the same temperature for 3 minutes. A solution of 122.8 mg of 6-fluoro-2-methanesulfonyloxymethylbenzothiazole [prepared as described in step (c) above] in 0.4 ml of dimethylformamide was then added to the reaction mixture. The temperature of the resulting mixture was then elevated to room temperature and the mixture was stirred for 3 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and an aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 38.3 mg (yield 28%) of the title compound as a solid having a melting point of 204° to 205° C.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([CH2:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:66])[C@@H:57]([OH:65])[C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:67]([OH:72])[CH2:68][C:69]([NH2:71])=O)[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:73])[CH2:28][CH2:29]2)[C:24](=[O:25])[NH:23][C@H:22](O)[C@H:21]([OH:75])[CH2:20]1)=[O:17])[CH3:7])[CH3:4].[CH2:76]([NH2:79])[CH2:77][NH2:78].B([O-])([O-])OC1C=CC=CC=1>>[CH3:1][CH2:2][CH:3]([CH2:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:66])[C@@H:57]([OH:65])[C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:67]([OH:72])[CH2:68][CH2:69][NH2:71])[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:73])[CH2:28][CH2:29]2)[C:24](=[O:25])[NH:23][C@H:22]([NH:78][CH2:77][CH2:76][NH2:79])[C@H:21]([OH:75])[CH2:20]1)=[O:17])[CH3:7])[CH3:4]
Reactant: NCCN
Reactant: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O
Agent: [O-]B([O-])Oc1ccccc1
Product: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](NCCN)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CCN)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O

Procedure:
In CN101792486A and CN 101648994A, a method has been disclosed, comprising the following steps: Pneumocandin B0 as the starting material reacts with ethylenediamine under the protection of phenyl borate, and then the amide group in the resulting intermediate is reduced to amine group to obtain caspofungin.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:15]Br.S([O-])([O-])=O.[Na+].[Na+]>CO>[Br:15][C:11]1[CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=[CH:9][C:10]=1[O:13][CH3:14]
Reactant: CCCCCCc1ccc(OC)cc1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCc1ccc(OC)c(Br)c1
Temperature: 25 °C

Procedure:
26.4 g (0.137 mol) of 4-n-hexyl-1-methoxybenzene was dissolved in 200 ml of methanol. 26.4 g (0.156 mol) of bromine was added while stirring under cooling with ice. The mixture was stirred for 2 hours, while raising the temperature to room temperature. Sodium sulfite was added to the reaction mixture to decompose an excess amount of bromine, whereupon the mixture was extracted with chloroform-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 20:1 mixture of n-hexane and ethyl acetate) to obtain 35.18 g (yield, 95.8%) of a colorless oil of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C1(C)C=CC=CC=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]4[CH2:26][CH2:25][CH2:24][O:23]4)=[CH:16][CH:15]=2)[CH2:6][CH2:5]3)[CH:36]=1
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CCc2cc(-c3cccnc3)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.00 g), toluene (10 ml) and Pd(PPh3)4 (2.69 g) was admixed with 3-pyridylboronic acid (0.28 g), ethanol (3 ml) and cesium carbonate solution (1.2 ml; 2 M in water). The mixture was boiled at reflux for 7 hours. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 428.54 (C27H28N2O3); MS (ESI): 429 (M+H+).
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3I)[O:6]1)[NH2:2].CCN(C(C)C)C(C)C.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([F:47])([F:46])[F:45])#[CH:37]>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[C:37]#[C:36][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:45])([F:46])[F:47])[O:6]1)[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(I)ncnc21
Reactant: C#Cc1ccccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(C#Cc3ccccc3C(F)(F)F)ncnc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 85.3 %

Procedure:
To a solution of [(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl sulfamate (0.200 g, 0.402 mmol) in DMF (7 mL) was added DIPEA (0.176 mL, 1.01 mmol), 1-ethynyl-2-trifluoromethyl-benzene (0.224 mL, 1.61 mmol), CuI (0.0191 g, 0.101 mmol), and Pd(PPh3)2Cl2 (0.0282 g, 0.0402 mmol). The mixture was stirred at r.t. for 50 min, diluted with DCM (25 mL) and washed with saturated aq EDTA.Na2 (3×25 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (15 to 50% EtOAc/DCM) to isolate the title compound (0.185 g, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]=2[F:38])[C:13]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:12]1.Cl[C:44]([F:50])([F:49])C(OC)=O.[F-:51].[K+].[Br-].[K+]>O.CN(C=O)C>[CH2:39]([C:13]1[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:36])(=[O:37])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]=2[F:38])[C:15](=[O:16])[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[C:44]([F:50])([F:51])[F:49])[N:12]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Temperature: 120 °C
Reaction time: 15 h
Yield: 61.7 %

Procedure:
A mixture of 400 mg (0.606 mmol) of 2-(2-bromo-5-nitrophenyl)-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 31, Step C), 128 μL (175 mg, 1.21 mmol) of methyl chlorodifluoroacetate, 42 mg (0.73 mmol) of potassium fluoride, 116 mg (0.606 mmol) of cuprous iodide, 72 mg (0.606 mmol) of potassium bromide, and 1.2 mL of DMF was stirred under N2 at 120° C. in a sealed tube for 15 hours. The cooled mixture was diluted with water and extracted 3× with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated, and the residue was flash chromatographed on silica gel (elution with 6:1 hexane-EtOAc) to give 243 mg (62%) of the title compound as a stiff, pale yellow foam, mp 145° -146° C. [Subsequently eluted was 28 mg of the 2-chloro-5-nitrophenyl analog.] The desired product was homogeneous by TLC in 5:1 hexane-EtOAc; mass spectrum (FAB) m/e 656 (M+Li)+.
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C)C=O.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[C:13]#[N:14]>O>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[S:2][CH3:1])[C:13]#[N:14]
Reactant: C[S-]
Reactant: N#Cc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C#N)cc1F
Reaction time: 0.33 h

Procedure:
Sodium thiomethoxide (3.88 g, 55.3 mmol) was added to a dimethylformamide (100 mL) solution of 3,4-difluorobenzonitrile (7.00 g, 50.3 mmol) over 20 minutes under ice water cooling, and the mixture was further stirred for 20 minutes at the same temperature. Water (200 mL) was added to the reaction mixture, and the solid precipitated therefrom was collected by filtration and washed with water. Thus, a crude product of the title compound was obtained. The crude product thus obtained was dissolved in ethyl acetate, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Thus, the title compound (7.30 g, yield: 87%) was obtained.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2[CH:11]=CC=C[C:9]=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[C:44]3=[N:45][CH:46]=[C:47]([S:48]([N:51]4[CH2:54][CH2:53][C@H:52]4[C:55](O)=[O:56])(=[O:50])=[O:49])[N:43]3[C@:42]([CH3:71])([CH2:58][C:59]3[CH:64]=[CH:63][C:62]([C:65]4[CH:66]=[N:67][CH:68]=[N:69][CH:70]=4)=[CH:61][CH:60]=3)[C:41]2=[O:72])[CH:36]=[C:37]([Cl:39])[CH:38]=1.C(N)(C)C.[NH4+].[Cl-]>C(Cl)Cl>[CH:10]([NH:6][C:55]([C@@H:52]1[CH2:53][CH2:54][N:51]1[S:48]([C:47]1[N:43]2[C@:42]([CH3:71])([CH2:58][C:59]3[CH:64]=[CH:63][C:62]([C:65]4[CH:70]=[N:69][CH:68]=[N:67][CH:66]=4)=[CH:61][CH:60]=3)[C:41](=[O:72])[N:40]([C:35]3[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=3)[C:44]2=[N:45][CH:46]=1)(=[O:50])=[O:49])=[O:56])([CH3:11])[CH3:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@]1(Cc2ccc(-c3cncnc3)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CC[C@H]3C(=O)O)n21
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)[C@@H]1CCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reaction time: 18 h

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′,-tetramethyluronium tetrafluoroborate (0.016 g), (i-Pr)2EtN (0.013 mL) and (S)-1-[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-azetidine-2-carboxylic acid (0.023 g, 0.04 mmol) were combined in CH2Cl2 (2 mL) at room temperature. Isopropyl amine (0.0064 mL) was then added and the reaction was stirred for 18 h. The reaction was diluted with CH2Cl2 and poured into saturated aqueous NH4Cl.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[NH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][NH:11][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: COC(=O)c1ccccn1
Reactant: NCCO
Product: O=C(NCCO)c1ccccn1

Procedure:
A mixture of 72 parts of methyl 2-pyridinecarboxylate and 32 parts of 2-aminoethanol is stirred and refluxed carefully for 2 hours. The reaction mixture is cooled and poured onto water. The product is extracted five times with trichloromethane. The combined extracts are dried, filtered and evaporated, yielding 49 parts of N-(2-hydroxyethyl)-2-pyridinecarboxamide as a residue.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:7](=[O:24])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[CH2:30](O)[CH3:31]>[H][H].[C].[Pd]>[CH:1]1([C:4]2[CH:5]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:7](=[O:24])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:30][CH3:31])[CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc([N+](=O)[O-])c3)ccn2c1=O
Reactant: [H][H]
Agent: [Pd]
Product: CCNc1cccc(-c2ccn3c(=O)c(C(=O)OCC)cc(C4CC4)c3c2C)c1

Procedure:
39 mg of ethyl 1-cyclopropyl-9-methyl-8-(3-nitrophenyl)-4-oxo-4H-quinolizine-3-carboxylate (Example 13) was dissolved in 2 ml of ethanol. 5 mg of 5% palladium carbon was added to the obtained solution, and they were stirred at room temperature in hydrogen atmosphere for 14 hours. The catalyst was taken by the filtration. Water was added to the filtrate. After the extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=100/1) to obtain 22 mg of ethyl 1-cyclopropyl-8-(3-ethylaminophenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][CH:15]([CH3:34])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]>>[CH3:14][CH:15]([CH3:34])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:13])([F:12])[F:1])[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)CCCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (4-methylpentyl)amide, the title compound was obtained as a white solid (65.5% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.86, 7.74-7.72, 7.62-7.54, 7.36-7.34, 6.98, 4.08-3.98, 3.92-3.65, 3.47-3.4, 3.35-3.31, 1.62-1.53, 1.28-1.21, 0.86. 13C NMR (75 MHz, CDCl3) δ 167.5, 162.9, 159.9, 145.3, 134.2, 132.3, 129.4, 127.0, 126.7, 126.2, 125.4, 121.7, 112.5, 46.3, 44.5, 44.3, 41.2, 39.6, 35.9, 27.7, 27.4, 22.4. MS (ES+) m/z 464.5 (M+1).