Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([O:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:32])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:38]1[C:37]2[CH:42]=[CH:43][C:34]([CH2:33][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[C:21]([O:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:32])[CH2:12][CH2:13]3)=[CH:35][C:36]=2[O:41][CH2:40][CH2:39]1
Reactant: CNC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To 2 mL of a chloroform solution containing 87 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-((methylamino)carbonylmethyloxy)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 49 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)-N-methylacetamide as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH2:24])=[S:23])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].Br[CH2:31][C:32](=O)[CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[S:23][CH:31]=[C:32]([CH2:33][CH2:34][N:35]3[C:39](=[O:40])[C:38]4=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]4[C:36]3=[O:45])[N:24]=2)=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2nc(CCN3C(=O)c4ccccc4C3=O)cs2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
A mixture of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}thioacetamide (2.19 g) and 1-bromo-4-phthalimido-2-butanone (1.48 g) in ethanol (50 ml) was heated under reflux for 4 hours and then evaporated. The residue was triturated with ether/hexane and the resulting solid collected, recrystallised from methanol and dried to give 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-(2-phthalimidoethyl)thiazole as a hemihydrate (1.73 g), m.p. 156°-157° C. Found: C,59.71; H,5.06; N,6.31. C32H29ClN3O7S.0.5H2O: requires C,59.58; H,4.80; N,6.51%.
Reaction SMILES: CO[C:3]([C:5]1[C:6]2[NH:7][C:8](=[O:27])[C:9]([CH3:26])([CH3:25])[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[C:15]1[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:16]=1[O:23]C)=[O:4].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[C:14]1[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:25])([CH3:26])[C:8](=[O:27])[NH:7]3)[C:3](=[O:4])[O:21]2
Reactant: COC(=O)c1c(-c2c(OC)cccc2OC)ccc2c1NC(=O)C(C)(C)N2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC1(C)Nc2ccc3c(c2NC1=O)c(=O)oc1cccc(O)c13
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Quinoxalinone vii (420 mg, 1.14 mmol) was dissolved in dry CH2Cl2 (10 mL) and cooled to −78° C. under an atmosphere of N2. BBr3 (536 μL, 5.68 mmol) was added dropwise. After the addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was cooled to −78° C. and MeOH (3 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure and then diluted with water (30 mL) and extracted with EtOAc (7×50 mL). The organic layers were combined and solvent was removed under reduced pressure to provide crude product (350 mg) as a yellow solid. A small portion of the crude material was purified by reverse phase preparative HPLC for characterization, the rest of the crude was used directly for the next step without any further purification. 1H NMR (CD3OD) δ 8.74 (d, J=9 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 7.13 (t, J=9 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 1.33 (s, 6H). Anal. Calcd for C17H14N2O4 ⅙CF3COOH: C, 63.22; H, 4.34; N, 8.51. Found: C, 63.54; H, 4.50; N, 8.32.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][CH:8]([F:12])[C:9](O)=[O:10].[CH3:13][C:14]([SH:17])([CH3:16])[CH3:15]>C(#N)C.[Co](Cl)Cl>[F:7][CH:8]([F:12])[C:9](=[O:10])[S:17][C:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)S
Reactant: O=C(O)C(F)F
Agent: Cl[Co]Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Product: CC(C)(C)SC(=O)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a solution of oxaloyl chloride (9.08 mL, 104 mmol) in acetonitrile (ACN) (50 mL) at 25° C. was added dropwise difluoroacetic acid (6.55 mL, 104 mmol). After 3 hours, 2-methyl-2-propanethiol (11.74 mL, 104 mmol) was added dropwise followed by cobalt(II) chloride (10 mg). After being stirred at room temperature for 18 hours, additional 2-methyl-2-propanethiol (4.0 mL, 35.4 mmol) was added. After 2 hours, the solution was poured onto Et2O (500 mL) and washed with saturated NaHCO3 (2×300 mL) and H2O (2×300 mL). The organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure to give a red oil. Vacuum distillation at 30 mm Hg gave S-tert butyl difluoroethane-thioate (8.26 g, 47% yield) as a colorless oil: bp 59°-63° C. (30 mm Hg); 1H NMR (CDCl3) δ 1.48 (s, 9H), 5.67 (t, 1H, J=54 Hz); 13C NMR (CDCl3) δ 29.45, 49.32, 108.94 (t, J=255 Hz), 191.23 (t, J=28 Hz); 19F NMR (CDCl3) δ-123.65 (d, J=55 Hz); IR (film, cm-1) 2969, 1684, 1154, 1093, 1064. Anal. Calcd for C6H10F2OS: C, 42.84; H, 5.99. Found: C, 43.06; H, 6.15.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[CH3:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[F:25][C:23]([F:26])([CH3:24])[CH2:22][O:21][C:17]1[N:16]=[CH:15][C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])=[CH:19][C:18]=1[CH3:20]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(C)(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(C)(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (93 mg, brown solid) from 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-73, single enantiomer) and phenyl formate (64 mg, 0.52 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[CH:10](Cl)(Cl)Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N+:4]#[C-:10]
Reactant: ClC(Cl)Cl
Reactant: Cc1cccc(Cl)c1N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: [C-]#[N+]c1c(C)cccc1Cl

Procedure:
The procedure of Example 1 was again followed, using 100 g (0.7 mole) of 2-methyl-6-chloroaniline, 75 ml of chloroform, 100 ml of methylene chloride, 175 ml of 50% aqueous sodium hydroxide, and 1 g of benzyltriethylammonium chloride. The product was a solid weighing 44 g, with structure confirmed by mass spectroscopy.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:7]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(N2CCOCC2)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
Compound 39 (391 mg, 1.00 mmol) was dissolved in NMP (10 mL), morpholine (1.05 mL, 12.0 mmol) was added thereto, followed by stirring at 150° C. for 8 hours. The reaction mixture was purified through silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:3) to afford the entitled Compound 40 (118 mg, 27%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=O.[CH3:14][NH2:15]>O1CCCC1>[CH3:14][NH:15][C:3]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=[O:2]
Reactant: COC(=O)c1cc(SC)cc(N)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(SC)cc(N)n1

Procedure:
A solution of 0.099 g 6-amino-4-methylsulfanyl-pyridine-2-carboxylic acid methyl ester in 2 ml methylamine 2M in tetrahydrofuran was kept at room temperature for 24 h. The solvents were evaporated and the residue was recrystallized from water to yield 0.054 g of the title compound as white crystals melting at 89-91° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:27][C:23]1[CH:22]=[C:21]([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cccc(-c2ccc(O)cc2)n1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cccc(-c2ccc(OCc3cccc(F)c3)cc2)n1
Yield: 76.4 %

Procedure:
A solution of ethyl 6-(4-hydroxyphenyl)-2-pyridinecarboxylate (D2, 100 mg, 0.41 mmol), 1-(bromomethyl)-3-fluorobenzene (117 mg, 0.62 mmol) and potassium carbonate (138 mg, 1.0 mmol) was stirred at 60° C. for 4 h. Then the solvent was evaporated under reduced pressure and the resulting crude material was purified by chromatography on silica gel using ethyl acetate/cyclohexanes (1:1) to afford the title compound (110 mg, 76%); MS: (ES/+) m/z: 352 [MH+], C21H18FNO3 requires 351; 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.05 (d, 2H), 8.0 (m, 1H), 7.80 (d, 2H), 7.35 (m, 1H), 7.20 (m, 2H), 7.05 (d, 2H), 7.00 (m, 1H), 5.15 (s, 2H), 4.50 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: C([Li])CCC.[O:6]=[C:7]([CH3:28])[CH:8]=[P:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:29]([CH2:36][CH2:37]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CCCCCC.O1CCCC1.[2H]C(Cl)(Cl)Cl.C(OCC)C>[O:6]=[C:7]([CH2:28][CH2:37][CH2:36][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:8]=[P:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [2H]C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCCOc1ccccc1
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
A solution of n-butyl lithium (2.69 g) in hexane (26.25 ml) was added dropwise to a stirred solution of 2-oxopropylidenetriphenylphosphorane (12.73 g) in anhydrous tetrahydrofuran (400 ml) at -65° C. in an atmosphere of dry nitrogen. The red solution was stirred at -65° C. for a further 15 minutes and was then treated with a solution of 2-phenoxyethyl bromide (8.04 g) in anhydrous tetrahydrofuran (40 ml). The mixture was stirred at 0° C. for one hour and then at ambient temperature for 2 hours, and was poured into water and extracted with diethyl ether. The organic solution was washed with water then dried over magnesium sulphate. Evaporation of the solution gave a yellow gum which slowly hardened on prolonged storage after trituration with diethyl ether to give crude 2-oxo-5-phenoxypentylidenetriphenylphosphorane (8.0 g), m.p. 83°-89° C. [elemental analysis: P, 7.4%; C29H27O2P requires P, 7.1%. νmax 715, 755, 1110, 1400, 1445, 1490 and 1555 cm-1. NMR (approximately 10% w/v solution in deuterochloroform): multiplets at 6.7-7.9δ and 1.8-2.7δ, triplet at 4.0δ (J=6 cycles/second)].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:18]C)=[CH:14][C:15]=2[CH3:17])[C:10]([CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:18])=[CH:14][C:15]=2[CH3:17])[C:10]([CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C)c2c(c1)c(C1CCN(C)CC1)cn2Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(Cc3ccccc3)c12
Yield: 60.2 %

Procedure:
By a method similar to Preparation 8, using 1-benzyl-5-methoxy-7-methyl-3-(1-methylpiperdin-4-yl)-1H-indole (1.62 g) and pyridine hydrochloride (25 g) to afford 0.936 g (60%) of the title compound: Mass spectrum (ion spray): m/z=335 (M+1).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>C1COCC1>[CH2:14]([C:11]1[S:10][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:8])=[C:13]([B:27]([OH:28])[OH:26])[CH:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccc(S(=O)(=O)NC(C)(C)C)s1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
5-Butylthiophene-2-sulfonic acid tert-butylamide (2.9 g, 0.010 mol, see step (a) above) was dissolved in THF (40 mL) under N2 and then cooled to −78° C. n-BuLi (1.6 M, 16.2 mL, 0.026 mol) was added via a syringe. The reaction mixture was stirred at −20° C. for 4 hours. Tri-iso-propylborate (13.3 mL, 0.058 mol) was then added via a syringe and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with 2 M HCl (20 mL). The organic phase was separated and the water phase was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine and dried and concentrated in vacuo. The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C:9]3[S:10][C:11]([CH2:14][OH:15])=[N:12][C:13]=3[C:4]=2[CH:3]=1.Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C:9]3[S:10][C:11]([CH2:14][O:15][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[N:12][C:13]=3[C:4]=2[CH:3]=1
Reactant: CN(C)CCCCl
Reactant: OCc1nc2c(s1)-c1ccccc1Sc1ccc(F)cc1-2
Agent: Cl
Product: CN(C)CCCOCc1nc2c(s1)-c1ccccc1Sc1ccc(F)cc1-2

Procedure:
By reacting the alcohol 80 (0.84 mmole) and 3-dimethylaminopropylchloride-hydrochloride (19 mmoles) an oily product was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH:10]=2)[CH:5]=1)(=O)[CH3:2].[C:19](#[N:23])[CH2:20][C:21]#[N:22].CCOCC>N1C=CC=CC=1>[C:21]([C:20]([C:19]#[N:23])=[C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH:10]=2)[CH:5]=1)[CH3:2])#[N:22]
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc2cc(N(C)CCO)ccc2c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCO)ccc2c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
0.51 g (2.1 mmol) of the third compound 3 is dissolved in 3 mL of dry pyridine to be added with 0.63 g (8.3 mmol) of malononitrile (CH2(CN)2). Reaction is processed under nitrogen to be heated at 70° C. with stirring for 4 hrs. After cooling, 50 mL of ether is added with sufficient stirring, where the part insoluble to ether is abandoned. The ether solution is washed with 50 mL of water. After being dried with anhydrous sodium sulfate and concentrated under reduced pressure, an organic phase is separated and purified by liquid chromatography (SiO2, CHCl3:EtOAc=1:1). Thus, a red solid product, 2-(1,1-dicyanopropen-2-yl)-6-[(2-hydroxyethyl)methylamino]naphthalene 4 (hereinafter referred to as fourth compound 4), is obtained, which has a weight of 0.46 g and a yield of 75.3%.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+]>C(O)C>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:34][CH:35]=1)([O:3][CH3:4])=[O:2]
Reactant: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)NCC(=O)O)cc1

Procedure:
A mixture of 26.4 g. of ethyl N-[4-(15-carbomethoxypentadecylamino)benzoyl]glycinate, 110 ml. of 1 N sodium hydroxide solution; and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The aqueous solution is washed with diethyl ether, acidified with 6 N hydrochloric acid, and filtered. The white solid is dried in vacuo and recrystallized from acetone to yield the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].C(N(CC)CC)C.[CH3:32][S:33][CH2:34]Cl>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([O:15][CH2:34][S:33][CH3:32])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: CSCCl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCSC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydro pyridine-3,5-dicarboxylic acid 5-methyl ester(3.32g), triethylamine(2.5ml)and chloromethyl methyl sulfide(0.9ml) in 30ml of acetonitrile was heated at 65° C. for 3 hours. The solvent was removed in vacuum, and then the residue was dissolved in ethylacetate. The ethylacetate solution was washed with water and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (ethylacetate:n-hexane=1:3). The eluent was concentrated in vacuum to afford a yellow solid which was recrystallized from methyl alcohol to give the titled compound(1.2g):
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[N:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.O>CC(O)=O.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[N:6]=[CH:7][CH:8]=[N:9]2
Reactant: O=[N+]([O-])c1cccc2nccnc12
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc2nccnc12
Yield: 61.3 %

Procedure:
To a three neck 250 mL round bottom flask equipped with a reflux condenser and nitrogen inlet was added 5-nitro-quinoxaline (4 g, 22.8 mmol) dissolved in HOAc (60 mL). The mixture was heated to boiling, removed from heat, and solid Fe powder (3.83 g, 68.6 mmol) was added. Vigorous boiling was observed. The reaction mixture was heated at reflux 10 minutes and then poured into H2O (100 mL) and ice. The aqueous solution was filtered and basified to pH>10 with 1 M NaOH, and extracted in EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting oil was purified by column chromatography (40% EtOAc/Hexanes) yielding 2.03 g (61%) of an orange solid: mp 87-90° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])=[O:17].O.O[Li].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])=[O:17]
Reactant: COC(=O)c1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1

Procedure:
Methyl 4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-nitrobenzoate (5.4 gr, 11.6 mmol) was dissolved in THF (78 mL) and water (52 mL) and treated at room temperature with LiOH hydrate (730 mg) for 24 hours. THF was evaporated and the resulting aqueous phase was treated with 5% KHSO4 aqueous solution (100 mL). The so obtained precipitated was filtered off and dried under vacuum at 60° C. affording the title compound without any further purification.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[OH:1][CH:2]([CH2:3][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16]
Reactant: O=C1NCCc2c(OCC3CO3)cccc21
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C1NCCc2c(OCC(O)CN3CCCCC3)cccc21
Yield: 66.7 %

Procedure:
A mixture of 3.0 g (13.7 mmol) of 3,4-Dihydro-5-(2-oxiranylmethoxy)-1(2H)-isoquinolinone, 1.4 g of piperidine (13.7 mmol), and 30 ml of ethanol was heated at reflux for five hours. The mixture was concentrated and the residue was recrystallized from ethanol/acetone (2/3) to give 2.78 g (67%) of the desired product; mp 162°-164°.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([C:10]3[C:18]4[O:17][C:16]([F:20])([F:19])[O:15][C:14]=4[CH:13]=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([NH2:40])=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([NH:40][C:2]3[N:21]=[C:5]4[C:6]([C:10]5[C:18]6[O:17][C:16]([F:20])([F:19])[O:15][C:14]=6[CH:13]=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: FC1(F)Oc2cccc(-c3cccn4nc(Cl)nc34)c2O1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cccc6c5OC(F)(F)O6)cccn4n3)cc2CC1

Procedure:
2-Chloro-8-(2,2-difluoro-1,3-benzodioxol-4-yl-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.71 g, 3.0 mmol) and 2,2-difluorobenzo[1,3]dioxole-4-boronic acid (0.64 g, 3.2 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.63 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.84 (d, J=7.5 Hz, 1H), 7.78-7.67 (m, 2H), 7.33-7.23 (m, 2H), 7.36 (d, J=6 Hz, 1H), MS=310 (MH)+. 243b) 7-[8-(2,2-difluoro-1,3-benzodioxol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2,2-difluoro-1,3-benzodioxol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (0.78 g, 2.5 mmol), and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.99 g, 3.778 mmol), in a manner analogous to Example 2d. Product was isolated as a foam (0.78 g, 58%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (d, J=6 Hz, 1H), 7.61 (d, J=6 Hz, 1H), 7.51-7.42 (m, 4H), 7.00-6.89 (m, 3H), 6.79 (s, 1H), 3.62-3.45 (m, 4H), 2.84-2.74 (m, 4H), 1.52 (s, 9H). MS=536 (MH)+.