Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.N1C=CC=CC=1>O>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1ccccc1Oc1ccccc1)N1CCCC1
Reaction time: 5 h

Procedure:
7.7 parts of 2-phenoxybenzoyl chloride was added dropwise to a solution of 2.5 parts of pyrrolidine in 20 parts of pyridine at 0°. When the addition was complete the mixture was stirred for 5 hours. The temperature was then allowed to rise to room temperature and the reaction mixture was poured into 100 parts of water. The aqueous solution was then extracted with chloroform, and washed with water. The chloroform layer was dried over magnesium sulfate, removal of the magnesium sulfate by filtration and concentration of the filtrate gave 6.4 parts of N-(2-phenoxybenzoyl)pyrrolidine, NMR (CDCl3) 1.8δ(m,4H,CH2), 3.4δ(m,4H-N-CH2), 7.1δ(m,9H,Aromatic H). The following compounds can be prepared from the 2-substituted benzoyl chloride and the appropriate secondary amine as described above.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Cl[CH2:20][CH2:21][CH2:22]Br.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K]>C(O)C.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:20][CH2:21][CH2:22][N:28]2[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]2=[O:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(Cc2ccccc2)CC1
Yield: 102.5 %

Procedure:
44 g benzylpiperazine, 200 ml absolute THF, 39.4 g 1-chloro-3-bromopropane and 76 g triethylamine are heated for 8 hours under reflux. After separating the precipitate the tetrahydrofuran is concentrated by evaporation, the residue is dissolved in 500 ml ether, treated twice with carbon and subsequently the solvent is removed by distillation. After distillation in a high vacuum 1-benzyl-4-(3-chloropropyl)piperazine with a boiling point of 145°-148° C./0.3 mm Hg is obtained. 22.75 g of this distillate was dissolved in 200 ml ethanol and admixed with 15 g potassium phthalimide and it was heated for 56 hours under reflux. Subsequently the solvent was evaporated, the residue was dissolved in 150 ml dichloromethane and the organic phase was washed three times with 50 ml two molar sodium hydroxide solution and three times with 50 ml water. Afterwards the organic phase was dried and evaporated. 30 g 2-[3-(4-benzylpiperazin-1-yl)propyl]isoindol-1,3-dione is obtained as a viscous oil. TLC (mobile solvent: heptane/methyl ethyl ketone/ammonia atmosphere 2:1), Rf=0.32.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([C:8]([F:11])([F:10])[F:9])[CH2:5][N:4]([C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[CH:14]=O)[CH2:3]1.[NH:23]1[C:30](=[O:31])[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25]>CO>[CH3:1][C@@H:2]1[C@H:3]2[C:29]3([CH2:14][C:13]4[C:12]([N:4]2[CH2:5][C@H:6]([C:8]([F:10])([F:9])[F:11])[O:7]1)=[CH:19][CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=4)[C:27](=[O:28])[NH:26][C:24](=[O:25])[NH:23][C:30]3=[O:31]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](C(F)(F)F)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: C[C@H]1O[C@@H](C(F)(F)F)CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]12
Temperature: 80 °C
Reaction time: 0.43 h

Procedure:
2-[cis-2-methyl-6-(trifluoromethyl)morpholin-4-yl]-5-nitrobenzaldehyde (212 mg, 0.67 mol) is combined with barbituric acid (95 mg, 0.67 mmol, Aldrich) in a vial with MeOH (3 mL). The sealed reaction is heated to 80° C. on a shaker block for 21 hours and then the solvent is removed by rotary evaporation. The product is purified on a Biotage Flash 25M+ using a 26 minute linear gradient of 2.5%-10% MTBE in CH2Cl2 eluent. The product is dried under vacuum yielding a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01, 2.93, 3.46, 3.66, 3.73, 4.04, 4.40, 4.48, 7.10, 7.88, 8.01, 11.63, 11.94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1NN=C(c2ccc(Cl)cc2)CO1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=C1OCC(c2ccc(Cl)cc2)=NN1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Step C (47.48 mmoles) in acetonitrile (260 ml) there are added 1-bromomethyl-4-nitro-benzene (52.23 mmoles) and potassium carbonate (189.92 mmoles). The reaction mixture is stirred at reflux for 4 hours under nitrogen. The reaction mixture is brought to ambient temperature and then diluted with 500 ml of DCM and 100 ml of water. Extraction with DCM (2×200 ml) is carried out and then the organic phases are combined. The organic phase obtained is washed with saturated NaCl solution and is then dried over sodium sulphate, filtered and concentrated to about 75 ml. After formation of a precipitate in suspension, ethyl ether (150 ml) is added, and stirred is carried out overnight at ambient temperature. The precipitate is filtered off, washed with ethyl ether and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1[N+:12]([O-])=O.C[O:16][CH:17]([O:21][CH3:22])N(C)C.O.NN.[CH3:26]N(C)C=O>CO.[Ni]>[CH3:22][O:21][C:17]([C:5]1[CH:4]=[C:3]2[C:2]([CH:1]=[CH:26][NH:12]2)=[C:10]([CH3:11])[CH:9]=1)=[O:16]
Reactant: COC(OC)N(C)C
Reactant: CN(C)C=O
Reactant: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C)c2cc[nH]c2c1
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A solution of 4,5-dimethyl-3-nitrobenzoic acid (Helv. Chim. Acta 1980, 37, 385; 2.50 g, 12.8 mmol) and N,N-dimethylformamide dimethyl acetal (3.66 g, 30.7 mmol) in N,N-dimethylformamide (25 mL) was heated at 140° C. for 4 h, then volatile material was removed by distillation. The residue was taken up in tetrahydrofuran (10 mL) and methanol (10 mL), then Raney nickel (aqueous suspension, 1 mL) and hydrazine hydrate (1.85 g, 57.6 mmol) were added over 30 min in three portions at 50° C., and the reaction was kept at 50° C. for another 90 min. The reaction mixture was filtered through diatomaceous earth, the filtrate was dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate 2:1) produced 4-methyl-1H-indole-6-carboxylic acid methyl ester (1.68 g, 69%). White solid, MS (ISP): m/e 190.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH:57]=[CH:56][N:55]=[CH:54]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:37]=[C:38]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:53]3[CH:57]=[CH:56][N:55]=[CH:54]3)=[CH:44][CH:45]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: c1c[nH]cn1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCn2ccnc2)CCC3)cc1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
A solution of 0.220 g (0.298 mmol) (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 9(a)] and 0.30 g (0.446 mmol, 1.50 equiv.) of imidazole in 1.8 ml of absolute N,N-dimethylformamide was stirred for 4 h at 80° C. The reaction was allowed to warm to room temperature, poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of diethyl ether. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 20:1 v/v mixture of dichloromethane/methanol as the eluent to yield 0.067 g (0.094 mmol, 31.5% of theory) of (3R,4R)-3-[1-(2-imidazol-1-yl-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 711 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][CH2:12][CH2:13][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: BrCCBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCc1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (5 g, 0.035 mol) in acetone (50 mL) was added 1,2-dibromoethane (15.6 mL, 1.3 mol) and potassium carbonate (13 g, 0.09 mol). The mixture was stirred at 80° C. for 48 hours. The salts were filtered and the mixture was evaporated. The crude obtained was partitioned between ethyl acetate/water. The organic layer was washed with sodium hydroxide 2N, water and brine, dried, filtered and the solvent was removed under reduced pressure to give the title compound as a white solid (73%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36]>ClCCCl>[C:2]1([CH2:1][NH:8][C:9]2[N:14]=[C:13]([NH:15][C:35]([C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)=[O:36])[C:12]([C:16]3[NH:17][N:18]=[N:19][N:20]=3)=[CH:11][N:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a solution of N2-Benzyl-5-(1H-tetrazol-5-yl)pyrimidine-2,4-diamine (27 mg, 0.1 mmol) in 1 mL of DCE, DIPEA (0.3 mmol, 3.0 eq.) was added followed by thiophene-2-carbonyl chloride (0.15 mmol, 1.5 eq.). The reaction was stirred at room temperature for 2 hours. The crude reaction mixture was concentrated down in vacuo, and the residue redissolved in ethylacetate. This organic solution was extracted several times with water, dried with magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give 4.8 mg of the desired compound. 1H-NMR (400 MHz, d6-DMSO): δ 9.07 (t, 1H), 7.81 (dd, 1H), 7.77 (dd, 1H), 7.36-7.29 (m, 4H), 7.28-7.23 (m, 1H), 7.16 (t, 1H), 4.45 (d, 2H). MS (EI) for C17H14N8OS: 379 (M+H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:11](Br)[CH:12]=[CH2:13]>C(OCC)C>[CH2:13]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH:12]=[CH2:11]
Reactant: c1ccc2c(c1)CCNC2
Reactant: C=CCBr
Solvent: CCOCC
Product: C=CCN1CCc2ccccc2C1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
To a 1L 3-necked round-bottomed flask, was added 100.0 g of 1,2,3,4-tetrahydroisoquinoline dissolved in 150 mL diethyl ether. The reaction mixture was cooled to 5° C. with an ice. While stirring, 45.4 g of allyl bromide in 60 mL diethyl ether was added slowly to the amine solution. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with 300 mL diethyl ether, and the white precipitate was removed by filtration. Ether was removed from the filtrate under reduced pressure using a rotary evaporator yielding 64.0 g of N-allyl 1,2,3,4-tetrahydroisoquinoline as a viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 61 g of N-allyl 1,2,3,4-tetrahydroisoquinoline dissolved in 100 mL diethyl ether. After cooling to 5° C. with an ice bath, 42.6 g of allyl bromide in 60 mL diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×500 mL). The washed solid was recrystallized from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 55.0 g of N,N-diallyl 1,2,3,4-tetrahydroisoquinolinium bromide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.ClC1C=CC(N2CCN(S(/C=C\CCC3N=CC(F)=CN=3)(=O)=O)CC2)=NC=1.[NH2:55][OH:56]>O1CCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:55][OH:56])[CH2:19][CH2:20][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NO
Reactant: O=S(=O)(/C=C/CCc1ncc(F)cn1)N1CCN(c2ccc(Cl)cn2)CC1
Agent: O=S(=O)(/C=C\CCc1ncc(F)cn1)N1CCN(c2ccc(Cl)cn2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(CC(CCc1ncc(F)cn1)NO)N1CCN(c2ccc(Cl)cn2)CC1
Reaction time: 18 h

Procedure:
To a solution of 2-((E)-4-[4-(5-chloropyridin-2-yl)piperazino]sulfonylbut-3-enyl)-5-fluoropyrimidine and 2-((Z)-4-[4-(5-chloropyridin-2-yl)piperazino]sulfonylbut-3-enyl)-5-fluoropyrimidine (0.44 g), in tetrahydrofuran (5 ml), was added hydroxylamine (1.0 ml, 50% aqueous solution). The mixture was stirred for 18 hours and then diluted with EtOAc(10 ml) and washed with saturated ammonium chloride solution(10 ml. The organic layer was dried over Na2SO4 and evaporated in vacuo to give 2-[4-[4-(5-chloropyridin-2-yl)piperazino]sulfonyl-3-(hydroxyamino)butyl]-5-fluoropyrimidine(0.483 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].O.[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.COC(OC)(C)C>CN(C)C=O>[CH3:12][C:11]1([CH3:16])[O:5][CH2:4][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(CO)(CO)CO
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(CO)(CO)CO1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Pentaerythritol (50 g, 0.36 mol) and p-toluenesulfonic acid monohydrate (0.61 g) were dissolved in 500 ml N,N-dimethylformamide (DMF, dried by molecular sieve at room temperature) at about 80° C., and then the mixture was allowed to cool undisturbed. When the solution cooled to about 40° C., stirring was started and 55.4 ml 2,2-dimethoxypropane (0.36 mol) was added. After 24 hours of stirring at room temperature, the solution was stirred at room temperature with 9.0 g of base treated DOWEX 1XZ-100 ion-exchange resin for 1 hour, filtered and then the solvent was evaporated under reduced pressure at 85° C. The base treated DOWEX 1XZ-100 ion exchange was prepared by washing 30 g. twice with 200 ml of deionized water, then washed with 300 ml of 4% aq. NaOH and then washed three times with 200 ml of water, filtered and then air-dried in a hood. After the treatment with this resin as noted above, the dry product was ground and extracted (Soxhlet), first with light petroleum ether (b.p. 40-60° C.) for 6 hours, then with diethyl ether for 12 hours, collected and dried. Yield: White crystals (40.0 g, 61.9%). M.P. 124.5°-125.5° C.; 11H-NMR (300 MHz, DMSO-d6) 1.28 ppm (s, 6H), 3.34 ppm (d, J=5.7 Hz, 4H), 3.58 ppm (s, 4H), 4.47 ppm (t, J=5.4 Hz, 2H);
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:30]=[C:29]([F:40])[C:28]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:47](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:28]3[C:29]([F:40])=[CH:30][C:31]([O:33][CH:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:32][C:27]=3[F:26])[N:46]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCOCC3)cc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(OC4CCOCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1
Yield: 27 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 188 as a white solid (12 mg, 27%). 1H NMR (400 MHz, d6-DMSO) δ 10.24 (s, 1H), 8.25 (dd, J=8.6, 3.9 Hz, 1H), 8.17-8.09 (m, 1H), 7.85 (s, 1H), 7.40-7.00 (br s, 2H), 7.20 (d, J=11.6 Hz, 2H), 5.30 (d, J=48 Hz, 1H), 4.92-4.86 (m, 2H), 4.11-4.00 (m, 2H), 3.92-3.84 (m, 2H), 3.75 (s, 3H), 3.62-3.50 (m, 3H), 2.07 (m, 4H), 1.95-1.70 (m, 2H), 1.68-1.55 (m, 2H). LCMS (ES+) m/z 564 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[N:8][O:9][C:5]=2[CH:4]=1.C(Cl)Cl.B(Br)(Br)Br.C(Cl)Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C(C)NC(C)=O)noc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)NC(C)c1noc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a suspension of N-[1-(6-methoxy-1,2-benzisoxazol-3-yl)ethyl]acetamide (500 mg, 2.13 mmol) obtained in Reference Example 9 in toluene (10 mL) was added 1 M boron tribromide methylene chloride solution (6.40 mL, 6.40 mmol) under ice-cooling and, under a nitrogen atmosphere, the mixture was stirred at room temperature for 1 hr. Methylene chloride (5 mL) and 1 M boron tribromide methylene chloride solution (5.00 mL, 5.00 mmol) were added thereto at room temperature, and the mixture was stirred under heating at 50° C. for 16 hr. To the reaction mixture was added ethyl acetate, and the mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (470 mg, quantitative) as an oil. This was used for the next step without purification.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([N+:8]1[C:12]2=[N:13][C:14]3[C:19]([N:20]=[C:11]2[N:10]([CH2:21][CH3:22])[C:9]=1[C:23]#[C:24][CH:25]=[C:26]1[N:38]([CH2:39][CH3:40])[C:29]2=[N:30][C:31]4[C:36]([N:37]=[C:28]2[N:27]1[CH2:41][CH3:42])=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:7].[CH2:43]([N:45]1[C:52](=[O:53])[CH2:51][C:49](=[O:50])[N:48]([CH2:54][CH3:55])[C:46]1=[S:47])[CH3:44].C(N(CC)CC)C.O>CN(C)C=O>[CH2:54]([N:48]1[C:49](=[O:50])[C:51](=[C:24]([CH:25]=[C:26]2[N:27]([CH2:41][CH3:42])[C:28]3=[N:37][C:36]4[C:31]([N:30]=[C:29]3[N:38]2[CH2:39][CH3:40])=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:23]=[C:9]2[N:10]([CH2:21][CH3:22])[C:11]3=[N:20][C:19]4[C:14]([N:13]=[C:12]3[N:8]2[CH2:6][CH3:7])=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:52](=[O:53])[N:45]([CH2:43][CH3:44])[C:46]1=[S:47])[CH3:55]
Reactant: CCN1C(=O)CC(=O)N(CC)C1=S
Reactant: CCN1C(=CC#Cc2n(CC)c3nc4ccccc4nc3[n+]2CC)N(CC)c2nc3ccccc3nc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1C(=O)C(=C(C=C2N(CC)c3nc4ccccc4nc3N2CC)C=C2N(CC)c3nc4ccccc4nc3N2CC)C(=O)N(CC)C1=S

Procedure:
A mixture of 1,3-diethyl-2-[(1,3-diethyl-1H-imidazo[4,5-b]quinoxalin-2-(3H)-ylidene)-1-propynyl]imidazo[4,5-b]quinoxalinium perchlorate) 0.33 g, 0.0005 mol) of Example 1, 1,3-diethyl-2-thiobarbituric acid (0.11 g, 0.0005 mol) and triethylamine (0.10 g, 0.001 mol) in dimethylformamide (5 ml), is heated at reflux for 30 seconds. After cooling the solution is diluted to 20 ml. with water. The dye is collected and washed with water. After recrystallization from acetonitrile, the yield of purified dye is 0.27 g (79%) - mp. indistinct.
Reaction SMILES: [C:1](O[K])(C)(C)C.P(=O)(OC=[N+]=[N-])OC.[CH3:15][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[CH:22]=[C:23]([CH:27]=O)[CH:24]=[N:25][CH:26]=1>C1COCC1>[C:27]([C:23]1[CH:24]=[N:25][CH:26]=[C:21]([CH:17]2[CH2:18][CH2:19][CH2:20][N:16]2[CH3:15])[CH:22]=1)#[CH:1]
Reactant: CC(C)(C)O[K]
Reactant: CN1CCC[C@H]1c1cncc(C=O)c1
Agent: CO[PH](=O)OC=[N+]=[N-]
Solvent: C1CCOC1
Product: C#Cc1cncc(C2CCCN2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of tBuOK in THF (0.08 mL, 0.08 mmol) cooled at −78° C. was added dropwise a solution of methyl diazomethyl phosphonate in THF (0.1 mL, 0.08 mmol). The solution was stirred at −78° C. for 5 min, then a solution of 5-(1-methylpyrrolidin-2-yl)pyridine-3-carbaldehyde (V) (0.0126 g, 0.066 mmol) in THF (1 mL) was added via a double tipped needle. The reaction mixture was stirred at −78° C. for 16 h then allowed to warm to RT over 2 h. After evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (silica gel, 10% EtOAC/hexanes) to afford 0.0061 g (51%) of 3-ethynyl-5-(1-methylpyrrolidin-2-yl)-pyridine (VI) as a clear oil. The data were identical to those described in the literature (Bleicher, L. S.; Cosford, N. P. D.; Herbault, A.; McCallum, J. S.; McDonald, I. A. J. Org. Chem. 1998, 63, 1109).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[C:4]([NH2:19])=[CH:3][CH:2]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(OC(C)=O)=O>CC(CC)=O>[C:20]1([NH:26][C:27]([NH:19][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[C:7]2[O:18][C:16](=[O:17])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccccc1-c1nc2ccccc2c(=O)o1
Temperature: 80 °C

Procedure:
A 250 ml three-neck bottle was charged under room temperature with 12.8 g [0.05 mol] anthranoylanthranilic acid and 100 ml methylethylketone. Under stirring 5.95 g [0.05 mol] phenylisocyanate was added and heated for about 4 hours under reflux about 80° C.). After this the suspension was cooled down to about. 40° C. Then 40 ml acetanhydrid was added and then heated additionally for 3 hours. After cooling down to 10° C. the precipitate was sucked off, washed with acetone and dried at 50° C. under normal pressure.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH2:18]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:14]1[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:13]=1)[CH3:19]
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: CCOC(=O)c1ccccc1-c1cnc(N)c(C(=O)Nc2ccncc2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate gives “A70”; method 1: HPLC/MS: 1.37 min, [M+H]=363;