Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[N:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:11]=1)=O.C(=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:10]2[CH:11]=[C:7]([C:5]3[CH:4]=[CH:3][N:35]=[C:36]([NH2:38])[N:37]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)=[N:9]2)=[CH:18][CH:17]=1
Reactant: N=C(N)N
Reactant: COc1ccc(Cn2cc(C(=O)/C=C/N(C)C)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Yield: 67.8 %

Procedure:
450 mg (1.1 mmol) of (2E)-3-(dimethylamino)-1-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]prop-2-en-1-one were dissolved in 10 ml of dry dimethylformamide and 1.2 g (6.66 mmol) of guanidine carbonate and 910 mg (6.66 mmol) of potassium carbonate were added. After 16 hours at 120° C. the solvent was removed in vacuo and the residue taken up with dichloromethane and washed with water. The organic phase was then dried over sodium to sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 9/1), giving 300 mg (68%) of the title compound.
Reaction SMILES: C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[N:28]=1.[CH3:39][O:40][C:41]1[C:49]2[O:48][CH2:47][CH2:46][C:45]=2[CH:44]=[C:43]([CH:50]=O)[CH:42]=1.C[Si]([C:56]#[N:57])(C)C>C1COCC1>[CH3:39][O:40][C:41]1[C:49]2[O:48][CH2:47][CH2:46][C:45]=2[CH:44]=[C:43]([CH:50]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[N:28]=[C:27]([CH3:26])[O:31][N:30]=3)=[CH:33][CH:34]=2)[C:56]#[N:57])[CH:42]=1
Reactant: COc1cc(C=O)cc2c1OCC2
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCC2

Procedure:
To a solution of 426 mg of Yb(OTf)3 in 30 ml of THF there were added 1.2 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 1.22 g of 7-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde [CAS No. 363185-46-0], 1 g of MS3A and 1.9 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of (7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].[ClH:12].Cl[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[C:4]([Cl:12])[C:3]=1[CH3:11]
Reactant: Cl
Reactant: Cc1cc(C=NO)ccc1Br
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1c(Br)ccc(C=NO)c1Cl
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
In a solution of 82.0 g of 4-bromo-3-methylbenzaldoxime in 450 ml of tetrahydrofuran, 120.0 g of concentrated hydrochloric acid was added a dropwise with stirring under ice cooling over 45 minutes. Then, 220 ml of 8% sodium hypochlorite aqueous solution was carefully added dropwise over 75 minutes so that the temperature of the reaction mixture would not exceed 5° C., after the completion of the addition, continued to stir at 10° C. or less further for 90 minutes. After the completion of the reaction, nitrogen gas was blown through the reaction mixture for 45 minutes and precipitated insoluble material was filtered off, and tetrahydrofuran was distilled off under reduced pressure. The remaining aqueous solution was extracted with 240.0 g of ethyl acetate. The organic phase was washed with water (240 ml×2) and then insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 93.5 g of the aimed product as pale yellow crystal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([Cl:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:16])=[C:7]([Cl:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Cl)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h

Procedure:
4-tert-Butyl-2-chloro-6-nitro-phenol (0.214 g, 0.934 mmol) was dissolved in 3 mL acetone and K2CO3 (0.65 g, 4.7 mmol) and MeI (0.58 mL, 9.3 mmol) were added. The reaction was stirred at 65° C. overnight, after which the solvent was removed under reduced pressure. The residue was taken up in DCM, the organic layer was washed with water, dried over MgSO4 and concentrated to yield 0.15 g of target product.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[F:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:29]=1[CH:30]=O.C(Cl)Cl.CO>C1COCC1>[N+:36]([C:34]1[CH:33]=[CH:32][C:29](/[CH:30]=[CH:5]/[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)=[C:28]([O:27][CH2:26][CH2:25][F:24])[CH:35]=1)([O-:38])=[O:37]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1OCCF
Reactant: Cc1ccc2nc(-c3ccc(CO[PH](=O)[O-])cc3)cn2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc([N+](=O)[O-])cc4OCCF)cc3)cn2c1
Yield: 74.6 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (60% dispersion in mineral oil, 27 mg, 0.67 mmol), diethyl[4-(6-methylimidazo[1,2-a]pyridin-2-yl)benzyl phosphonate (200 mg, 0.559 mmol) and 2-(2-fluoroethoxy)-4-nitrobenzaldehyde (119 mg, 0.559 mmol) in dry THF (15 ml) to give the title compound (174 mg, 74%) as an orange solid after work-up and flash chromatography (50:1 DCM/MeOH).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N)CN.C1COCC1.[Li]>O>[CH2:10]1[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: NCCN
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)CC1=C2CCCC1
Yield: 90.1 %

Procedure:
30 g (0.18 mol) of fluorene was placed in a 1 L glass vessel, to which a mixed solution of 175 mL of ethylenediamine and 175 mL of THF was added under a nitrogen atmosphere, and dissolved by stirring. 5.6 g (0.812 mol) of metallic lithium was added to the resulting solution at 0° C. over 50 minutes. After completing the reaction, water was added thereto, and the target compound was extracted with diethyl ether and rinsed with a sodium chloride aqueous solution. Magnesium sulfate was added to the diethyl ether layer, which was dried in a refrigerator overnight. Magnesium sulfate was filtered off, and diethyl ether was removed to provide 27.6 g of 1,2,3,4-tetrahydrofluorene (4HFluH) as an orange solid matter (yield: 90%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reaction time: 2 h

Procedure:
To (trans)-4-(aminomethyl)cyclohexanecarboxylic acid (10 g, 44.5 mmol) in 1,4-dioxane (75 ml) and water (75 ml) was added dropwise benzyl chloroformate (6.99 ml, 49.0 mmol). The pH was kept between 7 and 8 by adding saturated aqueous sodium carbonate. After stirring for two hours the reaction mixture was concentrated in vacuo till half volume, 1M sodium hydroxide (aq) was added till pH=9 and the mixture was extracted with diethylether. 2M Hydrochloric acid was added till pH=1 was the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to yield (trans)-4-((benzyloxycarbonylamino)methyl)cyclohexanecarboxylic acid (12.03 g)
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:30]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: CC(C)(C)OCc1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)OCc1cccc(-c2ccc3cnc(Nc4cccc(N5CCOCC5)c4)nn23)c1
Yield: 56.1 %

Procedure:
Analogous to Example 1510b, 7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (109 mg, 0.37 mmol) and 3-Morpholin-4-yl-phenylamine (0.0818 g, 0.459 mmol) were reacted to afford [7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-morpholin-4-yl-phenyl)-amine as an orange foam (95 mg, 56%). LCMS: 458 (M+H); 1H-NMR (DMSO-d6): 9.30 (s, 1H), 8.97 (s, 1H), 8.06 (s, 1H), 7.98 (d, 1H, J=7.74 Hz), 7.46 (t, 1H, J=7.74), 7.36 (d, 1H, 7.74 Hz), 7.30 (s, 1H), 7.28 (d, 1H, J=9.68 Hz), 7.15 (d, 1H, J=8.07 Hz), 7.12 (d, 1H, J=4.84 Hz), 6.95 (d, 1H, J=4.84 Hz), 4.48 (s, 2H), 3.65 (t, 4H, J=4.58 Hz), 2.95 (t, 4H, J=4.58 Hz), 1.22 (s, 9H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.O[C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH2:38][CH2:37][CH2:36]2>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]([C@@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])[CH2:38][CH2:37][CH2:36]2
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: O=C1NCC[C@@H]1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCC[C@H]1N1CCCc2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −20° C., N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) was added dropwise to a solution of (S)-3-hydroxypyrrolidin-2-one (500 mg, 5.0 mmol) in CH2Cl2 (8 mL). Trifluoromethanesulfonic anhydride (0.88 mL, 5.25 mmol) was added dropwise to this solution. Upon completion of addition, the mixture was stirred at −20° C. for 30 min. 6-Chloro-1,2,3,4-tetrahydroquinoline (1.26 g, 7.5 mmol) was added in one portion. The reaction was allowed to warm up to RT overnight. After 18 h, the reaction mixture was washed with saturated aqueous sodium bicarbonate (2×20 mL), brine (20 mL), dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 0-30% ethyl acetate in hexane gave (R)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)pyrrolidin-2-one as a colorless oil (150 mg, 12%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=251.3; tR=2.77 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1>C(NCC)C.C(Cl)Cl>[CH2:2]([N:3]([CH2:4][CH3:5])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:7]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)c1ccc([N+](=O)[O-])cn1
Yield: 195.5 %

Procedure:
A stirred mixture of 27.6 g (0.174 mole) of 2-chloro-5-nitropyridine in 500 ml of diethylamine was heated at reflux for two days. The excess diethylamine was removed by distillation under reduced pressure, leaving a residue. This residue was dissolved in methylene chloride, and the organic solution was washed with an aqueous, 10% sodium hydroxide solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 33.2 g of 2-diethylamino-5-nitropyridine as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12
Product: Cc1csc2nc(-n3cncn3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH3:11])[C:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)=[O:4].Cl.[N:13]1([C:19](=[O:34])[CH2:20][CH:21]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](O)=[O:23])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:3]([C@@H:2]([NH:1][C:22](=[O:23])[CH:21]([CH2:20][C:19]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:34])[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH3:11])=[O:4]
Reactant: O=C(O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Reactant: CC[C@H](N)C(=O)c1ncco1
Agent: Cl
Product: CC[C@H](NC(=O)C(CCCc1ccccc1)CC(=O)N1CCOCC1)C(=O)c1ncco1

Procedure:
It is similarly prepared according to the general procedure for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one; hydrochloride as the amino component and 2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid as the acidic component but without further oxidation.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.I(O)(=O)(=O)=[O:15].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH:1]1([S:4]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=[N+]([O-])c1ccc(SC2CC2)cc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
179 mg (1.11 mmol) of iron(III) chloride was added to a mixture of 7.2 g (36.88 mmol) of 1-cyclopropylsulfanyl-4-nitrobenzene in 140 ml acetonitrile and it was stirred for 15 minutes at room temperature. Then 9.25 g (40.57 mmol) of periodic acid was added in portions at 25° C. The mixture was stirred for 30 minutes and then added, while stirring, to a cooled saturated sodium thiosulfate solution. It was then extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 1:1). 5.93 g (28.07 mmol; yield: 76%) of the product was obtained.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([N:6]3[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]/[C:2]/3=[N:1]\[S:30]([CH3:29])(=[O:32])=[O:31])[S:8][CH:9]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CO/C(=N\S(C)(=O)=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 8 h
Yield: 6.4 %

Procedure:
4-[2-(2-Imino-4,4-dimethyl-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (0.250 g, 0.83 mmol), prepared in Example 63, was dissolved in tetrahydrofuran (2 mL), followed by triethylamine (0.139 mL, 1 mmol) and methanesulfonyl chloride (0.154 mL, 2 mmol). The mixture was stirred overnight, filtered and the tetrahydrofuran was removed in vacuo. Purification by normal phase HPLC on a phenomenex cyano column and eluting with hexane/1,2-dimethoxyethane (9:1 to 1:9) gave the title compound (0.020 g, 6%). HRMS: calcd for C16H16N4O3S2+H+, 377.07366; found (ESI, [M+H]+), 377.0722. HPLC purity 97.0% at 210-370 nm, 8.5 min; 97.1% at 244 nm, 8.5 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:33]([NH:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])(=[O:35])[CH3:34]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 89 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-acetylamino-ethyl)-amide (44 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), N-(2-amino-ethyl)-acetamide (34 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 494. 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (s, 1H), 7.98 (m, 2H), 7.81 (s, 1H), 7.64 (d, 1H), 7.51 (br, 1H), 7.35 (m, 1H), 7.25 (d, 1H), 3.62 (s, 3H), 3.22 (t, 4H), and 1.81 (s, 3H), —NH proton signal was not observed.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([CH2:18][OH:19])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O.O>[OH:19][CH2:18][C@@H:15]1[CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](CO)CC[C@H]2C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1CC[C@H]2CNCCN2C1
Yield: 92.2 %

Procedure:
A solution of 5.84 g (21.6 mmol) of (7S,9aS)—N—BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (WO 93/25552) in 140 mL of trifluoroacetic acid and 60 mL of water was stirred at room temperature for 16 h. The mixture was concentrated and the residue dissolved in water. The aqueous phase saturated with solid sodium carbonate and extracted with chloroform (3×). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give 3.39 g (92%) of the title compound. This material was used without further purification for subsequent reactions. 13C NMR (base, d-6 DMSO): δ 24.8, 25.1, 36.0, 45.7, 51.9, 56.1, 56.7, 62.0, 62.7.
Reaction SMILES: O[CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(Cl)Cl.C(N(S(F)(F)[F:30])CC)C>[Cl-].[Na+].O>[CH2:14]([O:13][P:12]([CH:2]([F:30])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)([O:16][CH2:17][CH3:18])=[O:19])[CH3:15]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOP(=O)(OCC)C(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
To a mixture of diethyl α-hydroxy-4-nitrobenzylphosphonate (1.0 g) and chloroform (10 mL) was added diethylaminosulfur trifluoride (1.4 mL) at −78° C. and the reaction mixture was warmed to room temperature. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated and the residue was purified by preparative HPLC to give 4-[(diethylphosphono)(fluoro)methyl]nitrobenzene (0.1 g, yield 10%) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.N1C2C(=CC=CC=2)C[C:13]1=O.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:25][CH2:24]1.NC1C=CC=CC=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:13][NH:39][C:36]1[CH:35]=[CH:34][C:33]([NH:32][CH2:31][CH2:30][CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:38][CH:37]=1)[C:5](=[O:11])[NH:6]2
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: CN1CCN(CCCNc2ccc(N)cc2)CC1
Solvent: Nc1ccccc1
Product: Cc1cccc2c1C(=CNc1ccc(NCCCN3CCN(C)CC3)cc1)C(=O)N2

Procedure:
The named compound is prepared by substituting 4-methyl-1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (used for the preparation of Example 302) for aniline in the reaction of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11](O)=[O:12])=[CH:7]2.[CH2:25]([S:32][CH:33]([CH:36]([O:39][CH3:40])[O:37][CH3:38])[CH2:34][NH2:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:25]([S:32][CH:33]([CH:36]([O:37][CH3:38])[O:39][CH3:40])[CH2:34][NH:35][C:11]([C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=1)=[CH:3][C:2]=2[OH:1])=[O:12])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cc1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(OC)C(CNC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1)SCc1ccccc1
Temperature: 0 °C
Yield: 50.1 %

Procedure:
To an ice-cooled and stirred mixture of 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (2.1 g) and 2-(benzylsulfanyl)-3,3-dimethoxypropan-1-amine (2.9 g) in N,N-dimethylformamide (50 mL) were added 1-hydroxybenzotriazole (1.1 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g). After stirred at 4° C. to room temperature for 15 h, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate:hexane=35:65 to 60:40, volume ratio) to give light yellow crystals, which were washed with ethyl acetate-hexane to give the title compound (1.73 g, 50%) as pale yellow needles. MS 569 (MH+).
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:3][C:4]1[C:8]([NH:9][C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([F:19])([F:30])[F:31])=[S:29])=[CH:7][S:6][CH:5]=1
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: Nc1cscc1N
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cscc1NC(=S)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.8 g of 3,4-diaminothiophene dihydrobromide was added to a mixture of 0.74 g of N-ethyl-N,N-diisopropylamine in 40 ml of anhydrous THF, and the mixture was stirred at room temperature for 10 minutes, and then admixed with 0.58 g of 2-trifluoromethylphenyl isothiocyanate. The mixture was stirred at room temperature for 3 hours and at 40° C. for a further 10 minutes, and left to stand at room temperature overnight. After the solvent had been distilled off, the residue was admixed with water and extracted with ethyl acetate, and the insoluble fraction was filtered off. The organic phase was washed with water and dried over sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate.