Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1>O>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: C1OCOCO1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
To 153 ml of fuming sulfuric acid, containing 25% of SO3, 50 g (0.3 m) of terephthalic acid are added, in small portions, at 20-22° C., then to the mixture thus obtained 23 g (0.25 m) of 1,3,5-trioxane are added portionwise thereinto. The mixture is kept about 30 minutes under stirring, without cooling, then the temperature is brought to 135-140° C. and heating is continued for 2-2.5 hours, whereby the reaction is complete, as shown by a HPLC control. The reaction mixture is cooled to 0-2° C. and 1000 ml of cold water are added thereto without exceeding 20-23° C., by keeping in mind that, during the addition of the first 15-20 ml of water, exothermia occurs, whilst afterwards the temperature may be easily controlled. The mixture is kept 1 hour under stirring at 20-25° C., the product thus obtained is filtered, still moist triturated in 300 ml of water repeatedly until the reddish colour of the mother liquors disappears. After the third trituration, the pH of the mother liquors stabilizes at values ranging from 5 to 6. The product is dried in vacuo at 45-50° C. until constant weight to give 47.5 g of 5-carboxyphthalide with a titer and a purity (HPLC)>95%.
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:18][O:19][C:20]1([C:26]2[CH:27]=[C:28]([CH2:32]Br)[CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CC(N(C)C)=O>[CH3:18][O:19][C:20]1([C:26]2[CH:27]=[C:28]([CH2:32][CH:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])[CH:29]=[CH:30][CH:31]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: COC1(c2cccc(CBr)c2)CCOCC1
Reactant: COC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C(Cc1cccc(C2(OC)CCOCC2)c1)C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 53 %

Procedure:
A solution of benzyl methyl malonate (0.88 g, 4.22 mmol) in 3 mL of anhydrous DMA was added to a suspension of sodium hydride (0.11 g, 4.45 mmol) in 2 mL of anhydrous DMA at 5° C., and the reaction mixture was stirred for 40 min at 5° C. Then 3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene [prepared as described in U.S. Pat. No. 5,424,320] (1.21 g, 4.24 mmol) was dissolved in 6 mL of anhydrous DMA and added to this solution. The reaction mixture was stirred for 2 h at 5° C., and for 18 h at room temperature. The reaction mixture was quenched with water (100 mL). The aqueous solution was extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to give 0.93 g (53%) of benzyl methyl 2-[3-[(4-methoxy) tetrahydropyran-4-yl]phenylmethyl]malonate as a clear oil: HRMS: calcd for C24H28O6 413.1964, found 413.1952.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.O.[OH-].[Na+]>C(O)(C)C>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: O=C(CCl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: ClCc1csc(-c2ccc(Cl)cc2)n1
Temperature: 20 °C
Reaction time: 10 h

Procedure:
171.65 g (1.0 mol) of 4-chlorothiobenzamide are dissolved in 550 ml of isopropyl alcohol and 133.3 g (1.05 mol) of 1,3-dichloroacetone are added at a temperature of a maximum of 30° C. over a period of 3hours. The mixture is subsequently stirred at 40° C. for 5.5 hours and at 20° C. for 10 hours. In order to complete the reaction the mixture is then heated to 55° C. for 7.5 hours. The product is isolated by cooling to 10° C. and adding 950 ml of water. The pH value is adjusted to 4 to 5 using sodium hydroxide solution and the product is filtered off with suction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([CH3:21])=[CH2:20]>>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:20][C:19]([CH3:21])=[CH2:18])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=C(C)CBr
Reactant: CC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Product: C=C(C)CN(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
N-(tert-Butoxycarbonyl)glycine tert-butyl ester was reacted with 3-bromo-2-methylpropene according to Method B8b, Step 1 to give N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester. The ester was reduced according to Method B8b, Step 2 to give N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methylprop-2-ene. The alcohol was treated with p-toluenesulfonyl chloride according to Method B8b, Step 3 to give N-(tert-butoxycarbonyl)-N-(2-tosyloxyethyl)-1-amino-2-methylprop-2-ene. The carbamate was deprotected according to Method B8b, Step 4 to give N-(2-tosyloxyethyl)-2-methylprop-2-en-1-ammonium trifluoroacetate. The tosylate was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C5a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2methylprop-2-enyl)-1,3-oxazolidine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cn1ccc(CBr)n1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccn(C)n3)C2=O)cn1
Yield: 19 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)-1-methyl-1H-pyrazole. Yield 19%. MS M+H calculated 370.1. found 370. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.4 uM.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7](O)[CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[N:4]=1.P(Br)(Br)[Br:17]>C(Cl)Cl>[Br:17][C:7]1[CH:8]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=1
Reactant: BrP(Br)Br
Reactant: Oc1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Br)cc(C(F)(F)F)n1
Temperature: 0 °C

Procedure:
A mixture of 6 g 2,6-di(trifluoromethyl)-4-hydroxypyridine and 4.9 ml phosphorus tribromide was heated 15 min. at 140°-150° C. and 90 min. at 160°-170° C. The reaction mixture was cooled, 150 ml methylene dichloride added, and poured into ice-water. From the methylene dichloride layer there was isolated 3.5 g 4-bromo-2,6-di(trifluoromethyl)pyridine, colorless solid, m.p. 92°-95° C.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:15]=[C:14]([O:16]C)[C:13]([Cl:18])=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[C:11]2=[O:19].O>ClCCl>[Cl:5][C:6]1[CH:15]=[C:14]([OH:16])[C:13]([Cl:18])=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:19]
Reactant: COc1cc(Cl)c2c(c1Cl)C(=O)N(C(=O)OC(C)(C)C)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1NCCc2c(Cl)cc(O)c(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Boron tribromide (10 mL) was added to a cooled (0° C.) solution of tert-butyl 5,8-dichloro-7-methoxy-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (296f, 14.5 g, 45.4 mmol) in dry dichloromethane (100 mL). The mixture was stirred at room temperature overnight, then water (10 mL) was added, causing a precipitate to form. The precipitate was collected by filtration, washed with water (500 mL), and dried to give 5,8-dichloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (296g, 9.2 g, 95% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 8.17 (s, 1H), 7.13 (s, 1H), 3.25-3.23 (m, 2H), 2.83-2.80 (t, J=6.2 Hz, 2H). MS: 232 [M+1].
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7].O>C(Cl)(Cl)Cl>[Br:1][C:10]1[C:9]([O:12][CH3:13])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:3])[CH:11]=1
Reactant: COc1ccc(F)c(C=O)c1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Bromine (15 ml, 300 mmol) was added slowly to a solution of 2-Fluoro-5-methoxy-benzaldehyde (23.12 g, 150 mmol) in chloroform (500 ml), and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2–16% EtOAc in hexanes) to give the product. Yield: 20.7 g, 60%. 1H NMR (CDCl3) δ: 3.93 (s, 3H), 7.08–7.13 (m, 1H), 7.29 (d, J=12.4 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([C:27]2[CH:26]=[C:25]([C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:22]=2[O:21][C:16]2[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=2)=[CH:41][CH:40]=1)(=[O:38])=[O:37]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 4-(methylsulfonyl)phenyl boronic acid as in Example 38 to afford 0.062 g (48%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C31H27O6SF3 584, found 585 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH2:10][OH:11])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=1[CH:16]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:2]1([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[O:1][CH:16]([C:15]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:14]=2[Cl:13])[O:11][CH2:10]1
Reactant: CCCCOC(=O)C(C)(O)CO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1(C)COC(c2cc([N+](=O)[O-])ccc2Cl)O1
Yield: 101.6 %

Procedure:
19.4 g of n-butyl 2,3-dihydroxyisobutyrate are added to 18.6 g of 2-chloro-5-nitrobenzaldehyde and 0.5 g of p-toluenesulfonic acid in 250 ml of toluene, and the mixture is refluxed for 5 hours under a water separator. After the mixture has been cooled, the solvent is removed and the residue is dried under greatly reduced pressure. 35 g of 3-(5-methyl-5-n-butoxycarbonyl-1,3-dioxolan-2-yl)-4-chloronitrobenzene (oil) are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[NH:11][C@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:10]([NH:11][C@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(N[C@@H](C)C2CCCCC2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(N[C@@H](C)C2CCCCC2)c2cccc(N)c2)cc1
Yield: 100.2 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[(S)-1-cyclohexylethyl]amine (2.63 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.39 g) and sodium borohydride (1.14 g) were reacted, to afford the title compound (2.42 g) as a yellow oil.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH:20]=1)[NH2:19]>CN(C=O)C>[NH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][O:10][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH:20]=1)[NH2:19]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: N[C@@H](CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(OC[C@H](N)c2ccccc2)ccc1[N+](=O)[O-]

Procedure:
(R)-(−)-2-Phenylglycinol (5.043 g, 36.8 mmol) was placed in a 250-mL RBF and placed under a nitrogen atmosphere. DMF (100 mL) was added and the reaction was stirred until a clear, colourless solution resulted. NaH (2.206 g, 55.1 mmol) was then added, followed by DMF (10 mL) as a wash, producing a vigorous reaction (gas evolution). The reaction was stirred at room temperature until the gas evolution had subsided, leaving a reddish heterogeneous mixture. 5-Fluoro-2-nitroaniline (6.89 g, 44.1 mmol) was then added, followed by DMF (10 mL), which immediately produced a bright red colour. The reaction was left stirring at room temperature and monitored by LC-MS. The reaction was quenched by its addition to an Erlenmeyer flask containing ethyl acetate (200 mL) and dilute aqueous NaHCO3 (250 mL). The phases were separated in a separatory funnel, and the organic layer was washed with water (150 mL), then brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The reaction was then purified by silica gel column (5-75% EtOAc in n-heptane), yielding two fractions of high purity 5-[(2R)-2-amino-2-phenylethoxy]-2-nitroaniline, both contaminated with residual DMF, as a yellow-orange oil. LRMS (ESI) calc'd for (C14H16N3O3) [M+H]+, 274.1; found 274.1.
Reaction SMILES: [CH3:1][N:2]([CH3:15])/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([NH:12][CH3:13])=[N:9][C:8]=1[CH3:14])=[O:6].[Cl:16]N1C(=O)CCC1=O.CO>>[Cl:16]/[C:4](=[CH:3]\[N:2]([CH3:1])[CH3:15])/[C:5]([C:7]1[S:11][C:10]([NH:12][CH3:13])=[N:9][C:8]=1[CH3:14])=[O:6]
Reactant: CNc1nc(C)c(C(=O)/C=C/N(C)C)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: CNc1nc(C)c(C(=O)/C(Cl)=C/N(C)C)s1
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a well stirred solution of (E)-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl) prop-2-en-1-one (2 mmol) in 50 ml methanol N-chlorosuccinimide (2.5 mmol) was added. The reaction mixture was stirred for 30 minutes. The mixture was evaporated to dryness and the residue was purified by column chromatography using EtoAc to yield (Z)-2-chloro-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one as light yellow solid (43%). 1H-NMR (DMSO-d6) δ: 2.37 (s, 3H, CH3), 2.98 (s, 3H, CH3), 3.25 (s, 6H, 2×CH3), 6.43 (s, 1H, NH), 7.42 (s, 1H, CH). HR-MS (m/z): calcd for C10H14ClN3OS, 259.0546; found 260.0541 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:6]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)[CH:8]=1)#[N:2].FC(F)(F)C(O)=O.N>>[C:1]([C:3]1[CH:4]=[C:5]([NH:46][S:47]([CH3:50])(=[O:48])=[O:49])[CH:6]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:8]=1)#[N:2]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(C#N)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(C#N)cc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 67.3 %

Procedure:
(S)—N-(3-Cyano-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (145 mg, 0.20 mmol) was treated with trifluoroacetic acid (3.8 ml, 49 mmol) and a solution of ammonia (7N in methanol, 3.8 ml, 27 mmol) according to the method described in Example 27 to give 78 mg (66% yield) of the title compound. Purity 100%.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CN(C)CCCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(C)C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 460 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)cc1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 4-methylphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O3, 346.1; m/z found, 347.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.03 (s, 1H), 12.92 (s, 1H), 8.98 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.16 (d, J=7.9 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 2.37 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[NH:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=1)([O-:7])=[O:6].[CH3:16]O>>[CH3:16][O:14][C:13]([C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[NH:12][N:11]=1)=[O:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Yield: 88 %

Procedure:
Thionyl chloride (1 mL) was added to a solution of 5-nitro-3-pyrazolecarboxylic acid (9.800 g, 62.3 mmol) in anhydrous methanol (100 mL), the reaction mixture was heated to reflux overnight. The solvents was removed in vacuo, the residue was recrystallized from ethyl acetate and hexanes to give 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (9.42 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.38 (s, 1H), 3.99 (s, 3H). MS (ES+) m/z 170.0 (M+1).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH:3]=[CH:2]1.CCN(CC)CC.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:7][CH2:6]2)[CH2:1][CH:2]=[CH:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCC2(C1)CCNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC2(CC=CC2)CC1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 8-azaspiro[4.5]dec-2-ene (2.74 g, 20 mmol) in Et3N (4.2 mL, 30 mmol) and DCM (100 mL) at 0° C. was added dropwise benzyl chloroformate (3.4 mL, 24 mmol). After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was extracted several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) yielding the title compound (3.85 g, 71%) as a yellow oil: LCMS (ES) m/e 272 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[Cl:15][C:16]1[C:17]([O:25][CH3:26])=[CH:18][C:19]([O:23][CH3:24])=[C:20]([CH:22]=1)[NH2:21]>>[Cl:15][C:16]1[C:17]([O:25][CH3:26])=[CH:18][C:19]([O:23][CH3:24])=[C:20]([NH:21][C:11]([C@H:3]2[C@H:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:2]2([CH3:1])[CH3:14])=[O:13])[CH:22]=1
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Product: COc1cc(OC)c(NC(=O)[C@H]2[C@H](c3ccccc3)C2(C)C)cc1Cl
Yield: 65.5 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (500 mg, 2.63 mmol) and 5-chloro-2,4-dimethoxyaniline (493 mg, 2.63 mmol) were reacted as described under General Procedure D to furnish the title compound (620 mg, 66%) as a beige solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.78 (s, 1H), 7.30-7.19 (m, 5H), 6.53 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 2.83 (d, J=5.7 Hz, 1H), 1.86 (d, J=5.7 Hz, 1H), 1.42 (s, 3H), 0.97 (s, 3H). mp 160-162° C. ESIMS m/z [M+H]+ 360.2.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([NH:10][C:17](=[O:18])[C:16]2[CH:20]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 5-tert-butyl-1,3,4-thiadiazol-2-amine (1.57 g, 10 mmol) and 5-chloro-2-methoxybenzoyl chloride (2.05 g, 10 mmol) in CH2Cl2 (45 mL) at 0° C. was added dropwise triethylamine (1.7 mL, 12 mmol) and the reaction mixture was allowed to warm to ambient temperature for 12 h. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure to afford 3.2 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.43 (s, 9H), 3.88 (s, 3H), 7.22 (d, J=8.8 Hz, 1H), 7.45-7.76 (m, 2H), 12.43 (s, 1H). MS (DCI/NH3) m/z 326 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].Cl.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:38])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3cccnc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and nicotinoyl chloride hydrochloride.