Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([O:24]C(C)C)=[O:23].[OH-].[Na+].Cl>C(O)(C)C.O>[C:1]1([S:11]([CH2:21][C:22]([OH:24])=[O:23])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)CCl
Reactant: O=S(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)CS(=O)(=O)c1cccc2ccccc12
Temperature: 30 °C
Reaction time: 1 h

Procedure:
44 g of 1-naphthalenesulfinic acid, 17.4 g of potassium carbonate, and 34.4 g of isopropyl chloroacetate were suspended in 45 ml of isopropyl alcohol. The suspension was then heated under reflux for 3 hours, after which the reaction mixture was cooled to 30° C. A 20% aqueous solution of 13.8 g of sodium hydroxide was added to the reaction mixture. The reaction system was then stirred for 1 hour. The resulting solution was diluted with 58 ml of water. 58 ml of 35% hydrochloric acid was then added to the reaction mixture. The resulting crystal was then filtered off, and air-dried. The yield was 54.9 g (95.8% of theoretical value).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)([OH:3])=O.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[C:51]([C:55]1[CH:56]=[C:57]([NH:83][S:84]([CH3:87])(=[O:86])=[O:85])[C:58]([O:81][CH3:82])=[C:59]([NH:61][C:62]([C:64]2[N:65]([CH3:80])[C:66]3[C:71]([CH:72]=2)=[CH:70][CH:69]=[CH:68][C:67]=3[CH2:73][N:74]2[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]2)=[O:63])[CH:60]=1)([CH3:54])([CH3:53])[CH3:52]>CN(C)C=O.C(OCC)(=O)C.O>[C:51]([C:55]1[CH:56]=[C:57]([NH:83][S:84]([CH3:87])(=[O:86])=[O:85])[C:58]([O:81][CH3:82])=[C:59]([NH:61][C:62]([C:64]2[N:65]([CH3:80])[C:66]3[C:71]([CH:72]=2)=[CH:70][CH:69]=[CH:68][C:67]=3[CH2:73][N:74]2[CH2:75][CH2:76][N:77]([C:1](=[O:3])[CH2:4][N:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:78][CH2:79]2)=[O:63])[CH:60]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCNCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)CN5CCN(C(=O)OC(C)(C)C)CC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
110 mg tert-butyl 4-carboxymethyl-piperazine-1-carboxylate are dissolved in 2 ml N,N-dimethylformamide, combined with 135 mg O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) as well as 270 μl N,N-diisopropyl-ethylamine (DIEA) and stirred for 20 minutes. Then 200 mg 1-methyl-7-piperazin-1-ylmethyl-1H-indole-2-carboxylic acid-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide dihydrochloride are added, the mixture is stirred for 12 hours at ambient temperature and then divided between water and ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/(methanol/conc. ammonia 9:1) 99:1 to 90:10).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCNc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of N2-pentyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (543 mg) in dry chloroform (4.6 mL) was cooled to 0° C. and NBS (334 mg) was added. The mixture was stirred at room temperature for 10 mins. The reaction was taken up in DCM (30 mL) and was washed with water (30 mL). The organics were separated, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a viscous brown residue (627 mg) which was used crude in the next step.
Reaction SMILES: CC1N=C(C2C=CC=CC=2C([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=O)ON=1.[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[C:37]([CH:41]=1)[C:38]([OH:40])=O.Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[C:37]([CH:41]=1)[C:38]([NH:11][C@H:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=1)=[O:40]
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(F)ccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 8) from 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 61 mg, 0.28 mmol) and (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CCN(C(C)C)C(C)C.[NH2:23][CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]1[OH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:13])[NH:23][CH:24]1[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]1[OH:33])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC1Cc2ccccc2C1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1Cc2ccccc2C1O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
5-Chloro-1H-indole-2-carboxylic acid (116 mg, 0.67 mmol) was dissolved in DCM (10 ml) containing DIPEA (0.21 ml, 1.19 mmol) and 2-aminoindan-1-ol (Method 1; 101 mg, 0.67mmol) and HATU (247 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for approximately 18 hours. The resulting solution was washed with water (20 ml) and the aqueous layer extracted with DCM (2×20 ml). The organic extracts were combined, dried over magnesium sulphate and concentrated under reduced pressure to give the title compound (195 mg, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[NH:19]>C1(C)C=CC=CC=1>[CH:20]1([C:18]2[N:19]=[C:13]([CH:12]=[CH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:15][N:17]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: N=C(NO)C1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(C=Cc2nc(C3CCCCC3)no2)cc1OC
Reaction time: 1.25 h

Procedure:
To a solution of 1.43 g (6.9 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 22 mL of toluene, 1.21 g (7.5 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 22 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxycyclohexanecarboximidamide (compound of Example 59; 2 g, 14 mmol) in 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[O:20]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:26]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)=[O:27])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CCOCC3)ncc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol), tetrahydro-2H-pyran-4-carboxylic acid (1.43 mmol, 185 mg), N,N-diisopropylethylamine (384 mg, 2.98 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (543 mg, 1.43 mmol) were dissolved in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 48 hours. Water (1 mL) was added, and the mixture was concentrated, washed with methanol to give the product (45.2 mg, 21.0%). LCMS (ESI): RT (Min)=1.203, M+H+=365.0, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.15 (s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.14 (d, J=12.0 Hz, 2H), 3.92-3.88 (m, 2H), 3.36-3.32 (m, 2H), 2.81-2.80 (m, 1H), 2.23 (s, 3H), 1.71-1.66 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[C:32]([CH3:37])[CH:33]=5)[N:28]([CH3:38])[C:27]4=[O:39])[CH2:22][CH2:21]3)=[N:9][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11]2)=[CH:6][C:5]=1[OH:40])[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[C:32]([CH3:37])[CH:33]=5)[N:28]([CH3:38])[C:27]4=[O:39])[CH2:22][CH2:21]3)=[N:9][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11]2)=[CH:6][C:5]=1[O:40][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1O
Product: CCOC(=O)COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCC
Yield: 64 %

Procedure:
The same procedure as in Example 48 was repeated, except that 290 mg (0.53 mmol) of Compound 59 obtained in Example 59 was used in place of Compound 47 obtained in Example 47, and ethyl bromoacetate was used in place of methyl iodide, to give 216 mg (yield: 64%) of Compound 60 as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].Br.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:22]([N+:33]([O-:35])=[O:34])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]3=[O:17])[CH2:29][CH2:28]2)=[C:22]([N+:33]([O-:35])=[O:34])[CH:21]=1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NC1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(C)n1c(=O)n(CCCN2CCC(Nc3ccc(Cl)cc3[N+](=O)[O-])CC2)c2ccccc21
Yield: 100 %

Procedure:
A mixture of 105 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 71 parts of N-(4-chloro-2-nitrophenyl)-4-piperidinamine hydrobromide, 53 parts of sodium carbonate, 0.2 parts of potassium iodide and 320 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 98.5 parts (100%) of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([N:15]1[C:21](=[O:22])[C:20]2[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:19]=2[NH:18][C:17](=[O:28])[CH:16]1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH3:14].C(N(CC)CC)C>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([N:15]1[C:21](=[O:22])[C:20]2[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:19]=2[NH:18][C:17](=[O:28])[CH:16]1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(c1ccc(Cl)cc1N)N1C(=O)c2cc(I)ccc2NC(=O)C1c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Cl)ccc1C(C)N1C(=O)c2cc(I)ccc2NC(=O)C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
Acetyl chloride (15 μL, 0.212 mmol) was added at 0° C. under argon to a solution of 1,3-dihydro-4-[1-(2-amino-4-chlorophenyl)ethyl]-3-(4-chloropenyl)-7-iodo-1,4-benzodiazepine-2,5-dione (100 mg, 0.177 mmol), in tetrahydrofuran (5 mL) and chloroform (5 mL). Then, triethylamine (30 μL, 0.21 mmol) was added drop wise and the reaction mixture was allowed warm up to room temperature. After 30 minutes, the solution was concentrated under reduced pressure and the residue was petitioned between ethylacetate and 1N sodium bicarbonate. Organic layer was dried (Na2SO4), evaporated, and the residue was purified by column chromatography to give the title compound (49 mg, 45%) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.81 (d, J=6.8 Hz, 3H), 2.44 (s, 3H), 5.33 (s, 1H), 6.37 (q, J=6.8 Hz, 1H), 6.47 (d, J=8.4 Hz, 2H), 6.55 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 7.03 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.28 (br s, 1H), 8.54 (d, J=2.0 Hz, 1H), 9.94 (s, 1H). Mass spectrum (LCMS, ESI pos.): Calcd for C25H20Cl2IN3O3: 607; found: 608 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([O:13]C(N(C)C)N(C)C)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[O:13])[N:3]=1
Reactant: Cc1cccc(F)n1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Fluoro-6-methylpyridine (14.4 g, 0.13 mol) and tert-butoxybis(dimethylamino)methane (Bredereck's reagent; 34.9 g, 0.20 mol) are heated at 140° C. for 24 h. The reaction is cooled and diluted with THF (100 mL). Sodium periodate (75 g) in water (400 mL) is added at 0-5° C., and the reaction mixture is then stirred for 24 h at room temperature. The precipitate is filtered through celite, and the filtrate extracted 5× with diethyl ether. The combined ether layers are washed with water, brine, and dried (MgSO4). Most of the solvent is removed by concentration at 0° C. (by keeping ice in the bath) to provide 2-Fluoropyridine-6-carboxaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](I)[CH3:13].O[Li].O>CCO>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:13]
Reactant: CCI
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A 500 mL 3-neck flask fitted with a stir-bar, condenser, and an Ar inlet was charged with 4-amino-3-nitrophenol (12.0 g, 77.9 mmol), ethyl iodide (15.2 g, 8.00 mL, 97.3 mmol), LiOH.H2O (6.55 g, 156 mmol), and EtOH (120 mL). The resultant solution was heated at 60° C. overnight. Another 3 mL of ethyl iodide and 1 g of LiOH.H2O were added, and the mixture was stirred at 60° C. overnight again. The solution was cooled and partitioned with EtOAc (250 mL) and H2O (200 mL). The organic phase was washed with 1% aqueous LiOH (2×200 mL), H2O (200 mL), and brine (200 mL), filtered through phase separation paper, and concentrated in vacuo to a dark red solid. The crude solid was triturated with hexanes:EtOAc 8:1 (50 mL). The solid was filtered, pressed with rubber dam, and rinsed with hexanes (3×10 mL). The material was dried to give 10.7 g of 46a as a red solid (75%). 1H NMR (60 MHz, CDCl3): δ 7.5 (d, 1H), 7.0 (dd, 1H), 6.7 (d, 1H), 5.9 (bs, 2H), 4.0 (qt, 2H), 1.4 (t, 3H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 96% with a retention time of 4.2 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10]C=2)=[C:3]1[C:14]([O:16][CH3:17])=[O:15].ClCC(=O)CC(OC)=O.C1(N=C=O)C=CC=CC=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][N:43]=2)[C:38]([CH:45]=O)=[CH:37]1.N1CCCCC1>CO>[NH:36]1[C:44]2=[N:43][CH:42]=[CH:41][CH:40]=[C:39]2[C:38]([CH:45]=[C:6]2[O:5][C:4]([N:7]3[CH2:8][CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:3]([C:14]([O:16][CH3:17])=[O:15])[C:2]2=[O:1])=[CH:37]1
Reactant: COC(=O)C1=C(Nc2ccccc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: COC(=O)CC(=O)CCl
Solvent: O=C=Nc1ccccc1
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C1=C(N2CCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.6 %

Procedure:
To a solution of methyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in methanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration, then purified by preparative HPLC, collected former fraction to afford the titled compound as solid (0.0075 g, y. 11%).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:13])([CH3:12])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)=[C:28]([F:38])[CH:27]=1)[CH3:23]>CC(C)=O>[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][C:3]([CH3:13])([CH3:12])[CH3:2])[CH2:11][CH2:10]2)=[C:28]([F:38])[CH:27]=1)[CH3:23]
Reactant: CCOC(=O)c1ccc(OCCCCBr)c(F)c1
Reactant: CC(C)(C)CCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCCN2CCN(CCC(C)(C)C)CC2)c(F)c1
Yield: 90 %

Procedure:
1-(3,3-Dimethyl-butyl)-piperazine hydrochloride from Example E4 (874 mg, 3.7 mmol), potassium carbonate (2.5 g, 18.0 mmol) and potassium iodide (60 mg, 0.4 mmol) were added to a solution of 4-(4-bromo-butoxy)-3-fluoro-benzoic acid ethyl ester from Example E72.1 (1.4 g, 4.4 mmol) in acetone (35 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc to 1% 35% ammonia:10% methanol:89% EtOAc) to yield the title compound (1.35 g, 90%).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][NH:10][CH3:11])[N:8]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH:29]([CH3:31])[CH3:30])[NH:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O.C(N(CC)CC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH:29]([CH3:30])[CH3:31])[NH:16][C:17]([N:10]([CH3:11])[CH2:9][C:7]1[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=1)=[O:19]
Reactant: CNCc1csc(C(C)C)n1
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Yield: 72.1 %

Procedure:
A solution of 15.7 g (92 mmol) of 2-isopropyl-4-(((N-methyl)amino)-methyl)thiazole in 200 ml of THF was combined with a solution of 20.5 g (69 mmol) of N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester. The resulting solution was treated with 1.6 g of 4-dimethylaminopyridine and 12.9 ml (92 mmol) of triethylamine, heated at reflux for 2 h, allowed to cool, and concentrated in vacuo. The residue was taken up in CH2Cl2, washed extensively with 5% aqueous K2CO3, dried over Na2SO4, and concentrated in vacuo. The resulting product mixture was purified by silica gel chromatography using chloroform as an eluent to provide 16.3 g (54%) of the desired compound. 1H NMR (DMSO-d6) δ0.88 (d, J=7 Hz, 3H), 0.92 (d, J=7 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 2.05 (octet, J=7 Hz, 1H), 2.86 (s, 3H), 3.25 (heptet, J=7 Hz, 1H), 3.61 (s, 3H), 3.96 (dd, J=8, 7 Hz, 1H), 4.44 (AA', 2H), 6.58 (d, J=8 Hz, 1H), 7.24 (s, 1H). Mass spectrum: (M+H)+ =328.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CN(C=O)C.C(N(CC)CC)C.[F:23][C:24]1[CH:41]=[CH:40][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>C(OCC)(=O)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][S:36]([C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:27]2[CH:40]=[CH:41][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:31][CH:32]=1)(=[O:37])=[O:38])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of glycine tert butyl ester hydrochloride salt (5.9 g, 18 mmol) and DMF (20 mL) at 0° C. was added triethylamine (6.5 mL, 45 mmol) and 4-(4-fluoro-benzyloxy)-benzenesulfonyl chloride. After stirring for 1 h, the mixture was warmed to room temperature and stirred for an additional hour. The mixture was diluted with ethyl acetate, washed with 1M HCl, saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Trituration of the residue with ether-hexane afforded 10.8 g of [4-(4-fluoro-benzyloxy)-benzenesulfonylamino]-acetic acid tert-butyl ester as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[OH:13][C:12]1[C:11]([OH:17])=[N:10][C:4]2[C:5](=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:9]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: Oc1nc2cc(F)c(F)cc2nc1O
Temperature: 25 °C

Procedure:
A mixture consisting of 11.3 g. (0.0784 mole) of 4,5-difluoro-o-phenylenediamine (U.S. Pat. No. 4,264,600) and 80 ml. (0.589 mole) of diethyl oxalate was refluxed for a period of four hours to give a thick precipitate of product. The spent reaction mixture was then cooled to room temperature (~20° C.) overnight, filtered and the solid product so obtained was thereafter washed several times with diethyl ether and air-dried to constant weight to ultimately afford 15.5 g of pure 2,3-dihydroxy-6,7-difluoroquinoxaline, m.p. >310° C.. Mass Spectrum: m/e, 198 (P+).