Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(N(CC)CC)C.[Br:21][C:22]([CH3:27])([CH3:26])[C:23](Br)=[O:24]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:23](=[O:24])[C:22]([Br:21])([CH3:27])[CH3:26])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 91.2 %

Procedure:
2,4-Dinitrophenol (9.6 gm, 52 mmol) in 80 ml anhydrous tetrahydrofuran was placed under a nitrogen atmosphere and cooled in an icebath. To this was added triethylamine (5.80 g, 57 mmol) followed by the dropwise addition of bromoisobutyryl bromide (15.6 g, 67 mmol) in 20 ml anhydrous tetrahydrofuran over 5 min. After stirring for 4 h, the solids were filtered off and the solution concentrated, and then recrystallized from 100 ml methanol to give 15.8 g yellow solid, >99% pure by HPLC.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A degassed solution of 6-bromoindole (1.0 g, 5.1 mmol), 4-fluorobenzeneboronic acid (0.928 g, 6.63 mmol), potassium phosphate (2.7 g, 153 mmol) and palladium(0)tetrakis-(triphenylphosphine) (0.294 g, 0.255 mmol) in dimethylacetamide (50 mL) was heated at 120° C. for 14 hours. After cooling to room temperature, the mixture was diluted with water. The suspension was filtered, the solid washed with water and then dissolved in ethyl acetate (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:4) to give 0.411 g (38.2%) of the title compound as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]12[CH2:8][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]#[N:24])=[O:17]>>[CH2:12]([O:11][C:9]([C:5]12[CH2:8][C:2]([NH:1][CH2:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C:23]#[N:24])=[O:17])([CH2:3][CH2:4]1)[CH2:7][CH2:6]2)=[O:10])[CH3:13]
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: CCOC(=O)C12CCC(N)(CC1)C2
Product: CCOC(=O)C12CCC(NCC(=O)N3CCC[C@H]3C#N)(CC1)C2
Yield: 91.1 %

Procedure:
In a similar manner to Example 6, ethyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (50.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (59.3 mg) were used to obtain (2S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.1]hept-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (79.4 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.CC(C)([O-])C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[C:28]([C:33]2([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:35][CH2:34]2)[N:27]=3)=[C:20]([F:42])[CH:19]=1>C(O)C>[F:42][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:24]1[S:25][C:26]2[C:31]([N:32]=1)=[CH:30][CH:29]=[C:28]([C:33]1([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:34][CH2:35]1)[N:27]=2)[CH2:17][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1
Reactant: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CC(C)(C)[O-]
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)c1
Temperature: 70 °C

Procedure:
In a reactor tube was dissolved ethyl 4-pyrazolecarboxylate (0.0957 g, 0.683 mmol) methyl 4-imidazolecarboxylate (0.047 g, 0.37 mmol) in ethyl alcohol (2 mL). To this solution was added tert-butoxide (0.0656 g, 0.683 mmol) followed by 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.150 g, 0.341 mmol) and the reaction mixture was heated to 70° C. for 90 min. The solid observed was collected by filtration, rinsed with Et2O to afford ethyl 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-pyrazole-4-carboxylate. MS (ESI) m/z: calculated: 498.2; Observed: 499.0 (M++1).
Reaction SMILES: [F:1][C:2]1([F:14])[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[NH:4][C:3]1=[O:13].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>O>[F:14][C:2]1([F:1])[O:7][C:6]2[CH:8]=[C:9]([F:12])[C:10]([N+:20]([O-:22])=[O:21])=[CH:11][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C1Nc2ccc(F)cc2OC1(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Nc2cc([N+](=O)[O-])c(F)cc2OC1(F)F
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.5 g, 12.31 mmol) was dissolved in sulfuric acid (40 ml, 750 mmol). The reaction mixture was cooled to 0-5° C. Slowly nitric acid (1.761 ml, 39.7 mmol) was added dropwise and the temperature was maintained between 0-5° C. The reaction mixture was stirred for 30 min at this temperature. Then the reaction mixture was added dropwise to vigorously stirred cold water. A solid was formed, which was extracted with dichloromethane. The combined extracts were dried over Na2SO4, and concentrated to yield 2.56 g of the title compound as a brown solid. GC/MS m/e (M+)=248
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=O.Cl.[NH2:26]/[C:27](/[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1)=[N:28]/[H].[O-]CC.[Na+]>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:28]=[C:27]([NH:30][CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)[N:26]=2)[CH:13]=[CH:12][S:11]3)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(-c2nc3sccn3c2C(=O)C=CN(C)C)ccc1F
Reactant: [H]/N=C(/N)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Yield: 87.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one (0.537 g, 1.55 mmol) and tert-butyl 4-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride (0.650 g, 2.33 mmol) was diluted with 13 ml of absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of sodium ethoxide in ethanol (780 μl) to form a reaction mixture. The reaction mixture was heated to reflux for 24 hours. Volatiles were removed in vacuo and the residue was taken up in 50 ml of ethyl acetate and 50 ml of water. The phases were separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic extracts were washed with 100 ml of water, and then with a saturated sodium chloride solution (100 ml). The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product was purified by flash chromatography on silica gel (gradient 50% to 75% ethyl acetate in hexanes) to yield 0.713 g of a pale yellow solid (88%). 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.71 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.45 (d, J=4.3 Hz, 1H), 7.35 (dd, J=8.2, 2.0 Hz, 1H), 7.26 (dd, J=11.3, 8.2 Hz, 1H), 7.19-7.12 (m, 2H), 6.39 (d, J=5.1 Hz, 1H), 3.98-3.87 (m, 3H), 3.83 (s, 3H), 2.91 (t, J=11.5 Hz, 2H), 1.94-1.87 (m, 2H), 1.47-1.35 (m, 2H), 1.42 (s, 9H). LCMS: 525 [M+H].
Reaction SMILES: [C:1](O[C@@H](C1C(C)=CC2C(=CC=C(OS(C(F)(F)F)(=O)=O)C=2)C=1C1C=CC(Cl)=CC=1)C(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:48]=[C:47]2[C:42]([CH:43]=[C:44]([CH3:63])[C:45]([CH:56]([OH:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])=[C:46]2[C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)=[CH:41][CH:40]=1>>[C:1]([O:62][CH:56]([C:45]1[C:44]([CH3:63])=[CH:43][C:42]2[C:47](=[CH:48][C:39]([Cl:38])=[CH:40][CH:41]=2)[C:46]=1[C:49]1[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=1)[C:57]([O:59][CH2:60][CH3:61])=[O:58])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1

Procedure:
Ethyl 2-tert-butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetate was prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)acetate of Example 51, except using racemic ethyl 2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate. Material was carried on crude without further characterization.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[NH2:8].C(Cl)(Cl)Cl.[CH3:20][CH2:21]OCC>C(O)(=O)C>[CH3:13][C:10]([CH3:11])([CH3:12])[CH2:9][N:6]1[C:7]2[N:8]=[C:20]([CH3:21])[NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14]
Reactant: CCOCC
Reactant: CC(C)(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2CC(C)(C)C

Procedure:
10.4 g of 5,6-diamino-1-(2,2-dimethylpropyl)-2,4-(1H,3H)-pyrimidine dione (XXVIII) was refluxed in 75 ml of acetic acid for 1 hour. 50 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 11.4 g. The amide was refluxed in 50 ml of 1N NaOH for 1 hour and then neutralized with 5N HCl. Yield 7.2 g (XXXIV). NMR (see Table I).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH:15]=[C:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:30][CH:31]1[O:33][CH2:32]1)(=O)=O>O>[O:33]1[CH2:32][CH:31]1[CH2:30][O:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH:15]=[C:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18]
Reactant: O=C1OCCC1=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCCC1=Cc1ccccc1OCC1CO1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Dimethylformamide (30 ml) and potassium carbonate (4.4 g) were added to α-(2′-hydroxybenzylidene)-γ-butyrolactone (3 g), and a racemic compound of glycidyl nosylate (3.4 g) was added. The mixture was stirred at 50° C. for 3 hr. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give oily α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (3.2 g). This compound (0.4 g) was reacted in methanol with 4-(naphthalen-2-yl)piperidine (0.5 g) in the same manner as in Example 307 to give the title compound, melting point 127–128° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].Br[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:14][CH2:15][OH:16])[C:5]2=[O:12]
Reactant: OCCBr
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(Br)ccc2ncn1CCO

Procedure:
6-Bromoquinazolin-4(3H)-one Compound 178-A (1.0 g), 2-bromoethanol (1.1 g), and potassium carbonate (610 mg) were heated in DMA (10 mL) at 80° C. for 16 h. Reaction was extracted with water and dichloromethane (3 times), combined organic layers washed with brine, over sodium sulphate and concentrated. Residue was triturated with acetonitrile to yield 6-bromo-3-(2-hydroxyethyl)quinazolin-4(3H)-one Compound 178-B (810 mg) as a white solid. MS m/z (ESI)=268.9 (base peak, 79Br-M+H+); 270.9 (81Br-M+H+); 290.9 (79Br-M+Na+); 292.9 (81Br-M+Na+).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1
Reactant: O=C(O)c1cccc(Nc2ccccc2)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A mixture of 3-(phenylamino)benzoic acid (0.155 g, 0.727 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.168 g; 0.727 mmol), HATU (0.303 g; 0.799 mmol) and N,N-diisopropylethyldiamine (0.313 mL; 1.82 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.072 g (25%) of the title compound as a pink solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[C:3]=1[C:10]1[CH2:14][CH2:13][O:12][N:11]=1.[Br:15]Br>S(=O)(=O)(O)O>[Br:15][C:7]1[C:2]([CH3:1])=[C:3]([C:10]2[CH2:14][CH2:13][O:12][N:11]=2)[C:4]([S:8][CH3:9])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: CSc1cccc(C)c1C1=NOCC1
Agent: O=S(=O)(O)O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 10 g (48 mmol) of 3-(2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole are added a little at a time to 120 ml of conc. sulfuric acid, and the mixture is stirred for about 30 minutes. 3.7 g (23 mmol) of bromine are then added dropwise, and the mixture is stirred at 0° C. for 2.5 hours. The mixture is then allowed to warm to room temperature over a period of about 45 minutes. A homogeneous solution is formed. For work-up, the reaction mixture is poured onto ice-water and extracted three times with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried with magnesium sulfate and concentrated. This gives 11.4 g of crude product which is used for the next step without further purification.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:7])(C)(C)C.Cl.[C:32]([O:36][C:37]([NH:39][C@H:40](C(O)=O)[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH:20]([CH3:21])[CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:7])[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of 370 mg (0.87 mmole) of (2S, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2-isopropyl-N-butylhexanamide (prepared as described in Preparation 4) and 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with diethyl ether. The solvent was once again removed by distillation under reduced pressure. This operation was repeated three times, and the final residue was then dried in vacuo for 8 hours. At the end of this time, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran, and 260 mg (0.96 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the suspension. After this, 0.15 ml (0.99 mmole) of 95% diethyl cyanophosphonate and 0.27 ml (1.94 mmole) of triethylamine were added, in that order, to the suspension, whilst ice-cooling and under an atmosphere of nitrogen, after which the mixture was stirred for 6 hours. The reaction mixture was then freed from the solvent by evaporation under reduced pressure, and the resulting residue was purified by medium pressure column chromatography through silica gel (using a 20:1 by volume mixture of methylene chloride and methanol as the eluent) to afford 470 mg (yield 93%) of the title compound as white crystals, melting at 201°-203° C.
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=[CH:8][C:7]=2/[C:6](=[C:17](\OCC)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:46])[C:36](=[O:45])[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:31][CH:30]=1.N1CCCCC1>CN(C=O)C>[CH3:46][N:35]([C:32]1[CH:31]=[CH:30][C:29]([NH:28]/[C:17](/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=[CH:8][C:7]\2=3)=[CH:34][CH:33]=1)[C:36](=[O:45])[CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1
Reactant: CCO/C(=C1/C(=O)N(C(C)=O)c2cc(C(=O)OC)ncc21)c1ccccc1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1cc2c(cn1)/C(=C(/Nc1ccc(N(C)C(=O)CN3CCN(C)CC3)cc1)c1ccccc1)C(=O)N2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Step-2: To a solution of (E)-methyl 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (40 mg, 0.109 mmol) in DMF (0.2 mL) was added N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (28 mg, 0.109 mmol) at room temperature, and the reaction mixture was stirred at 110° C. for 2 h. The reaction mixture was cooled to RT, piperidine (0.2 mL) was added and stirred for 10 minutes at room temperature. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography using 5% CH3OH in dichloromethane as eluent to afford (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate as yellow solid. MS (ES+): m/z 541.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]=[C:10]1[C:22]2[CH:21]=[C:20]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][C:13]([S:27](Cl)(=[O:29])=[O:28])=[CH:14][CH:15]=2>N1C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][S:27]([C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[C:22](=[CH:21][C:20]([S:23]([NH:1][C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=5)(=[O:25])=[O:24])=[CH:19][CH:18]=4)[C:10](=[O:9])[C:11]=3[CH:12]=2)(=[O:29])=[O:28])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1c2cc(S(=O)(=O)Cl)ccc2-c2ccc(S(=O)(=O)Cl)cc21
Solvent: c1ccncc1
Product: O=C1c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc2-c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc21
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Aminophenol (0.91 g, 8.38 mmol) in pyridine was treated with 9-oxo-9H-fluorene-2,7-disulfonyl dichloride (1.58 g, 4.19 mmol, purchased from Maybridge) in one portion at 0° C. After two hours, the volatiles were removed at reduced pressure and the residue was partitioned between ethyl acetate and H2O. The organic layer was separated, washed with 1N HCl, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (8% CH3OH/CH2Cl2) to provide the title compound as a yellow solid (1.97 g, 90% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 2H), 9.50 (s, 2H), 7.97-8.11 (m, 4H), 7.92 (d, 2H), 7.0 (t, 2H), 6.49-6.64 (m, 4H), 6.43 (m, 2H); MS (DCI/NH3) 540 (M+NH4)+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:26]=1>C1(C)C=CC=CC=1>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[N:26]=[C:22]([CH:21]=[P:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(-c2csc(CBr)n2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2csc(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 60 °C
Yield: 13.2 %

Procedure:
Triphenylphosphine (4.82 g, 18.38 mmol) was added to a solution of 2-(bromomethyl)-4-(4-fluorophenyl)thiazole (5 g, 18.38 mmol) in toluene (30.0 mL) and the reaction was refluxed at 60° C. for 2 h. A precipitate was formed which was filtered and washed with ether (10 mL) thrice to provide 4-(4-fluorophenyl)-2-((triphenylphosphoranylidene)methyl)thiazole (1.1 g, 10.89%), which was carried through without further purification. MS (ESI) m/z: Calculated for C28H21FNPS: 453.11. found: 454.0 (M+H)+
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([C:25]2[CH:24]=[CH:23][C:22]3[O:17][CH2:18][CH2:19][O:20][C:21]=3[CH:26]=2)[OH:28])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc3c(c1)OCCO3)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2,3-dihydro-1,4-benzodioxine-6-carboxylic acid
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16](=O)(OC)OC>>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH3:16])(=[O:5])=[O:4]
Reactant: COC(=O)OC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: COS(=O)(=O)C(F)(F)F
Yield: 197.7 %

Procedure:
731 g (2.59 mol) of trifluoromethanesulfonic anhydride and 232 g (2.58 mol) of dimethyl carbonate are added to the residue, and the process described above is repeated. 837 g of methyl trifluoromethanesulfonate having a purity of greater than 99% are isolated (yield: 99.1%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1cc(N)no1
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)no1
Yield: 57.1 %

Procedure:
4.8 gm (0.015 mol) of 4-hydroxy-2-methyl-2H-naphtho [2,1-e]-1,2thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 2.11 gm (0.021 mol) of 3-amino-5-methyl-isoxazole in 250 ml of dry xylene analogous to Example 1, yielding 3.3 gm (57% of theory) of 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 253° C, after recrystallization from xylene.