Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CC#N>[CH:24]([N:7]1[CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]1[CH3:8])([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: CC1CN(c2ccc(C=O)cc2)CC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Yield: 45.9 %

Procedure:
To a mixture of 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 4.6 mmol) and K2CO3 (1.3 g, 9.2 mmol) in CH3CN (10 mL) was added 2-iodopropane (2.3 mL, 22.9 mmol) and the reaction was stirred at reflux temperature overnight. Additional 2-iodopropane (2.3 mL, 22.9 mmol) and K2CO3 (1.3 g, 9.2 mmol) were added and the reaction was continued to reflux overnight. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, to afford 4-(4-isopropyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.550 g, 46%).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12]CCCCCC>C1COCC1>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: C1CCOC1
Product: CC/C=C\CCCCCCCCO
Reaction time: 4 h
Yield: 40 %

Procedure:
In a glovebox, a 25 mL Schlenk flask was charged with oleyl alcohol (1.0 g, 3.7 mmol) and THF (2.5 mL). A solution of 1 (0.047 g, 2 mol %) in THF (0.5 mL) was added and the container was sealed and removed from the glovebox. The flask was attached to a Schlenk line and after three pump/refill cycles, under a positive pressure of argon, the Teflon plug was removed and replaced with a rubber septum. A needle was introduced into the flask and placed into the reaction solution. A slow bubble of 1-butene was introduced and the reaction was allowed to stir with bubbling 1-butene for 4 hours. The reaction was quenched with excess ethyl vinyl ether, and the solvent was removed in vacuo. Flash chromatography of the residue (SiO2, using a slow gradient of hexanes to 9% EtOAc in hexanes) provided 7 (0.27 g, 40% yield, 77% Z as determined by 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.29-5.45 (2H, m), 3.63 (2H, t, J=6.6 Hz), 1.94-2.06 (4H, m), 1.56 (2H, p, J=6.7 Hz), 1.29 (11H, m), 0.95 (3H, m); 13C NMR (CDCl3): δ 131.6, 129.3, 63.1, 32.8, 32.6, 29.8, 29.5, 29.4, 29.2, 29.1, 20.5, 14.4; HRMS (FAB): 184.1830, [C12H24O]+ requires 184.1827.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:15]([Cl:19])[C:16]=2[Cl:18])[CH2:11][C:10]1([CH3:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>S(=O)(=O)(O)O.C(O)(=O)C>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:15]([Cl:19])[C:16]=2[Cl:18])[CH2:11][C:10]1([C:25]1[CH:30]=[CH:29][C:28]([CH2:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6])=[CH:27][CH:26]=1)[CH3:31]
Reactant: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1(c2ccc(CNC(=O)CCl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
Well-pulverized N-hydroxymethyl-2-chloroacetamide (3.37 g., 0.0274 mole) is added portionwise to (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (10.0 g., 0.0274 mole) in 36N sulfuric acid (100 ml.) and acetic acid (100 ml.) with stirring at 40°-50° C. over one-half hours. Additional N-hydroxymethyl-2-chloroacetamide (1.68 g., 0.014 mole) is added over a four hour period until no starting material remains. After stirring at 25° C. for 16 hours the reaction mixture is added to crushed ice-water (2 l.) to precipitate 11.9 g. of {1-oxo-2-[4-(2-chloroacetamidomethyl)phenyl]-2-methyl-6,7-dichloro-5-indanyloxy}acetic acid which melts at 138°-141° C. and is used in the next step without purification.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1.[C-:23]#[N:24].[Na+]>O.Cl>[CH3:16][N:15]([CH2:14][CH2:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:23]#[N:24])=[CH:7][CH:8]=1)[C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)[CH3:17]
Reactant: CN(C)CCC(c1ccc(N)cc1)c1ncc[nH]1
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCC(c1ccc(C#N)cc1)c1ncc[nH]1
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A solution of sodium nitrite (0.3 g) in water (5 ml) was added dropwise to a stirred solution of 3-(4-aminophenyl)-N,N-dimethyl-3-(imidazol-2-yl) propanamine (1.0 g) in 2 N hydrochloric acid (6 ml) and water (6 ml), keeping the temperature at 3°-5°. After stirring for 30 min. the dark red solution was adjusted to pH 7-8 and treated with sodium cyanide (0.2 g) and cuprous cyanide (0.4 g) and heated on a steam bath for 3 h. The mixture was then adjusted to pH 11-12 and extracted with ethyl acetate (3×30 ml). The extracts were dried (Na2SO4) and concentrated to give the title compound as a gum (0.33 g) which was taken up into methanol (5 ml) and treated with a solution of maleic acid (0.15 g) in methanol (5 ml). Removal of the solvent and trituration of the residue with ether gave the dimaleate salt of the title compound as an off white solid that crystallised from ethanol-ether with m.p. 147°-148°; τ(D2O)2.06 to 2.35 (2H,m,aromatic),2.48(2H,br.s,imidazole), ##STR36## 6.5-7.5(4H,m,CH2CH2N(CH3)2),7.03(6H,s,N(CH3)2).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C([O-])([O-])=O.[Na+].[Na+].[OH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:31]2[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: OB(O)c1ccc(O)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(-c3ccc(O)cc3)c21

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 13), 2M aqueous Na2CO3 solution (0.26 mL), (Ph3P)2PdCl2 (21.2 mg, 0.026 mmol) and 4-hydroxyphenylboronic acid (53.9 mg, 0.39 mmol) in 1,2-dimethoxyethane (10 mL) was heated at 104° C. for 4 days. The reaction mixture was filtered and concentrated. The crude material was purified by reverse phase HPLC to give (Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 41 mg, 45%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH:1]1([CH2:7][CH2:8][C:9]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CCCCC1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC2CCCCC2)cc1
Temperature: -5 °C
Yield: 79.1 %

Procedure:
To a 250 ml three-necked flask were added 5.00 g (28.74 mmol) in theoretical amount of 3-cyclohexylpropionyl chloride prepared in the step 1, 3.11 g (28.74 mmol) methylphenyl ether and 150 ml dichloromethane. The resulting mixture was cooled in ice salt bath to −5° C., added portionwise 3.83 g (28.74 mmol) anhydrous AlCl3 under stirring, upon the completion of addition. The mixture was stirred at room temperature for 2 hours, poured into a mixture (150 g ice+5 ml concentrated hydrochloric acid), the organic layer was separated, concentrated under a reduced pressure to about 10 ml, the aqueous layer was extracted with ethyl acetate 2×50 ml, the organic phase was combined, washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain a pale brown solid, which was recrystallized with petroleum ether to obtain a 5.6 g product as a white solid in a yield of 79.1%, mp: 64-65 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.85˜1.00 (2H, m, CH2), 1.10˜1.40 (4H, m, 2×CH2), 1.61˜1.1.82 (7H, m), 2.92 (2H, t, J=7.56 Hz, COCH2), 3.87 (3H, s, OCH3), 6.23 (2H, d, J=8.68 Hz, ArH), 7.94 (2H, d, J=8.68 Hz, ArH); ESI-MS m/e (%): 269.2 (M+Na, 100), 247.2 (M+1, 71).
Reaction SMILES: [CH:1]1([C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1.C(Cl)(=O)C1C=CC=CC=1>>[C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2
Solvent: O=C(Cl)c1ccccc1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Yield: 79 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 100 mg, 0.50 mmol) and benzoyl chloride (64 μL, 0.56 mmol) were converted to the title compound (120 mg, 79%). 1H NMR (DMSO-d6) δ 7.70 (s, 1H), 7.65-7.60 (m, 3H), 7.57-7.49 (m, 4H), 7.24 (s, 2H), 4.07 (t, J=8.5 Hz, 2H), 3.15 (t, J=8.4 Hz, 2H); MS(ESI+) m/z 303.2 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[C:19]([CH:22]=1)[C:20]#[N:21]>C(N(CC)CC)C>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:16]=[CH:17][C:18]=1[O:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][OH:27])#[N:21]
Reactant: CC(C)(CO)COc1ccc(N)cc1C#N
Reactant: O=C(O)c1cc2ccccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(CO)COc1ccc(NC(=O)c2cc3ccccc3s2)cc1C#N
Yield: 30.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (0.77 g), 5-amino-2-(2,2-dimethyl-3-hydroxypropoxy)benzonitrile monohydrochloride (1.0 g) and triethylamine (0.6 ml), the title compound (0.45 g) was obtained. melting point: 188-189° C.
Reaction SMILES: CN(C)CCN.[CH:7]1([CH2:10][O:11][N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:9][CH2:8]1.C(O)(=O)C.[C:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])(=O)[CH3:28]>CCO>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:30]([C:27](=[N:12][O:11][CH2:10][CH:7]2[CH2:9][CH2:8]2)[CH3:28])[CH:35]=1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CC1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NOCC1CC1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(cyclopropylmethoxy)phthalimide (326 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (302 mg, 1.0 mmol) in EtOH (2 mL), and the mixture stirred for 48 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(1-cyclopropylmethoxyiminoethyl)phenyl]trifluoromethanesulfonamide 187 (300 mg, 81%), as a white solid. M.p. 53-54° C. 1H n.m.r. (400 MHz, CDCl3) δ 11.84, br s, 1H; 7.65, d, J=8.8 Hz, 1H; 7.49, d, J=2.4 Hz, 1H; 7.32, dd, J=2.4 and 8.8 Hz, 1H; 4.03, d, J=7.2 Hz, 2H; 2.34, s, 3H; 1.22, m, 1H; 0.64, m, 2H; 0.34, m, 2H.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]2[C:13](=[O:19])[CH:14]=[C:15](C=O)[O:16][C:11]=2[C:10]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)[CH2:26][C:27]([OH:29])=[O:28]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]2[C:13](=[O:19])[CH:14]=[C:15]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])[O:16][C:11]=2[C:10]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C=O)oc12
Solvent: c1ccncc1
Product: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C=CC(=O)O)oc12

Procedure:
7-Benzyloxy-4-oxo-8-propyl-4H-1-benzopyran-2-carboxaldehyde (3.2 g), from Example 1(c) and malonic acid (1.1 g) were heated in pyridine (15 ml) at 100° C. until gas evolution ceased. The mixture was then evaporated and the residue was extracted with sodium bicarbonate. Acidification gave the title acid. The same acid was also prepared by hydrolysis of the product of Example 1(d).
Reaction SMILES: Cl[C:2](=[N:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([C:16]1[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]2[C:28]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:21]=[C:20]2[N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl>[C:3]1([C:2]2[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][C:16]3[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]4[C:28]=3[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]4[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[O:10][N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCCCc1c2c(nn1CCC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCc1cc(-c2ccccc2)no1
Yield: 80 %

Procedure:
α-Chlorobenzaldoxime (0.64 g, 4.1 mmol) was added to a solution of di(tert-butyl) 1-pent-4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (prepared as described in Parts A-E of Example 57, 1.36 g, 2.76 mmol) and triethylamine (0.60 mL, 4.14 mmol) in dichloromethane (10 mL). The solution was heated at 40° C. for 19 hours, during which time additional α-chlorobenzaldoxime (0.65 g) was added. The reaction was worked up as described in Part B of Example 595. The crude product was purified by chromatography (silica gel, sequential elution with 20% then 40% ethyl acetate in hexanes) to provide 1.35 g of di(tert-butyl) 1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=S)[C:15]([C:24](OCC)=[O:25])=[N:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(O)C.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][NH2:40].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[C:24](=[O:25])[C:15]2=[N:14][N:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]2=[N:40]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: COCCOC
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-4-thioxo-1,4-dihydrocinnoline-3-carboxylate (160 mg, 0.410 mmol) was dissolved in 1,2-dimethoxyethane (2 mL) and absolute ethanol (1 mL). 2-Fluorophenylhydrazine (114 mg, 0.902 mmol, 2.2 equiv) and potassium carbonate (170 mg, 1.23 mmol, 3.0 equiv) were added. The mixture was stirred vigorously for 15 minutes at ambient temperature and then placed into an oil bath preheated to 98° C. for 7 hours. The mixture was cooled ambient temperature, diluted with chloroform and washed once with water. The aqueous layer was extracted once with chloroform and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 99:1; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.32 (1H, d, J=7.8 Hz), 7.90 (1H, s), 7.71-7.61 (4H, m), 7.60-7.52 (3H, m), 7.43-7.37 (3H, m), 7.31-7.26 (2H, m), 6.47 (1H, s), 5.88 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 437.1517 [(M+H)+; calculated for C25H18FN6O: 437.1521].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)([O-:8])=[O:7].[BH3-]C#N.[Na+]>CO>[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:5][CH2:4][C:3]#[N:2])([O-:8])=[O:7]
Reactant: N#CCN
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#CCNCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.5 %

Procedure:
2-aminoacetonitrile hydrochloride salt (3.67 g, 39.7 mmol) was added to a solution of 2-nitrobenzaldehyde (5.00 g, 33.1 mmol) dissolved in anhydrous MeOH (30 mL). The reaction was stirred at room temperature for 5 minutes to achieve solution. NaCNBH3 (2.08 g, 33.1) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then diluted with EtOAc (50 mL). The organics phase was washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated to give 4.20 g (22.0 mmol, 66% yield) of 2-(2-nitrobenzylamino)acetonitrile (1) as a tan oil 4.20 g (22.0 mmol, 66% yield). The material was used without purification in the next step.
Reaction SMILES: C1(C[N:8]2[CH2:12][C@@H:11]3[CH2:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[O:16][C@H:10]3[CH2:9]2)C=CC=CC=1.[ClH:21].[H][H]>CO.[Pd]>[ClH:21].[CH2:12]1[NH:8][CH2:9][C@@H:10]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][C@@H:11]12
Reactant: c1ccc(CN2C[C@@H]3Cc4ccccc4O[C@H]3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc2c(c1)C[C@H]1CNC[C@@H]1O2

Procedure:
To the compound of Example 5 (1.09 g) in methanol (40 ml) was added 10.9M hydrogen chloride in methanol (0.41 ml) and 10% palladium on charcoal (0.1 g). The mixture was hydrogenated at 50° until hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate evaporated to give a white solid. Recrystallisation from propan-1-ol gave the title compound (0.56 g) m.p. darkens from 225° and melts 265°-270° (d), NMR (DMSO-d6) τ 2.7-3.2 (4H, multiplets, aromatic), 5.85 (1H, m, 3a-H), 6.2-6.5 and 6.8-7.3 (6H, multiplets, 1-H2, 3-H2 and 9-H2), and 7.77 (1H, m, 9a-H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[CH3:18]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:18][N:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: Cc1cccc2ncc(-c3nnn[nH]3)c(=O)n12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cc1cccc2ncc(-c3nnnn3C)c(=O)n12
Temperature: 80 °C
Reaction time: 1 h
Yield: 66.53 %

Procedure:
A mixture of 2.3 g of 3- (1H-tetrazol-5-yl) -6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine, 50 ml of dimethylformamide, 1.38 g (0.001 mole) of anhydrous potassium carbonate and 2.85 g (0.02 moles) of methyl iodide was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with 150 ml of water. The precipitating crystals were collected. 1.61 g (66.53%) of the title compound was obtained, which was crystallized from dimethylformamide, m.p.: 232°-234° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:14]([CH2:15][OH:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:16][CH2:15][C:14]1[C:9]([Br:8])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccnc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccnc1Br
Reaction time: 1.5 h

Procedure:
Triethylamine (8.90 mL) is added to a round bottom flask containing a solution of (2-bromopyridin-3-yl)methanol (8 g, 42.55 mmol) in dichloromethane (212 mL) at 0° C., then methanesulfonyl chloride (3.95 mL) is added and the mixture is stirred at that temperature for 1.5 h. After that time the mixture is washed with water and organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure to yield 10.4 g of the title compound used without further purification. MS (m/z): 266, 268 (M+1; M+3).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:32])[CH2:10][C:11]1[CH:31]=[CH:30][C:14]2[O:15][CH:16]([CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[O:17][C:13]=2[CH:12]=1)C)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH:16]1[O:15][C:14]2[CH:30]=[CH:31][C:11]([CH2:10][CH:9]([NH:7][CH3:6])[CH3:32])=[CH:12][C:13]=2[O:17]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.41 g (0.89 mmol) of 1G in 2 mL of dichloromethane was added 2 mL of trifluoroacetic acid. The resulting solution was allowed to stir at room temperature for 90 minutes and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 20% methanol in ethyl acetate to give 0.29 g (0.64 mmol, 69%) of 1H as a colorless thick gum (M+Na, 357).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.[C:26]([NH:34][C:35]1[CH:47]=[C:46]([CH:48]=[CH2:49])[CH:45]=[CH:44][C:36]=1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[C:26]([NH:34][C:35]1[CH:47]=[C:46](/[CH:48]=[CH:49]/[C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[CH:45]=[CH:44][C:36]=1[C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
0.10 mL of 1-bromo-4-(trifluoromethoxy)benzene, 0.22 mL of tributylamine and 5.2 mg of palladium acetate were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.15 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred under nitrogen atmosphere at 110° C. for 3 hours. After the reaction mixture was cooled to room temperature, 0.07 mL of 1-bromo-4-(trifluoromethoxy)benzene, 0.11 mL of tributylamine and 5.2 mg of palladium acetate were added at room temperature and stirred under nitrogen atmosphere at 110° C. for 2 hours. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; toluene; ethyl acetate=20:1] to obtain 0.10 g of tert-butyl 2-(benzamido)-4-((E)-2-(4-(trifluoromethoxy)phenyl)vinyl)benzoate as white solid.