Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:35])([F:34])[C:12]1[CH:26]=[C:25]2[C:15]([C:16]([OH:33])=[C:17]([C:28](OCC)=[O:29])[C:18](=[O:27])[C:19]32[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=1.Cl.[C:37]([O:41][C:42](=[O:45])[CH2:43][NH2:44])([CH3:40])([CH3:39])[CH3:38]>O1CCOCC1.CCOCC>[F:10][C:11]([F:34])([F:35])[C:12]1[CH:26]=[C:25]2[C:15]([C:16]([OH:33])=[C:17]([C:28]([NH:44][CH2:43][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:45])=[O:29])[C:18](=[O:27])[C:19]32[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Temperature: 75 °C
Reaction time: 17 h
Yield: 79.6 %

Procedure:
DIPEA (0.931 mL, 5.35 mmol) was added to a mixture of ethyl 7-trifluoromethyl-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.32 g, 3.56 mmol) and glycine tert-butyl ester hydrochloride (0.717 g, 4.28 mmol) in dioxane (30 mL). The reaction mixture was stirred at 75° C. for 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the desired compound as a light yellow solid (1.29 g). MS (m/e)=456.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-]>>[F:13][C:9]1[CH:8]=[C:7]2[C:12]([CH2:2][CH2:3][C:4](=[O:5])[NH:6]2)=[CH:11][CH:10]=1
Reactant: O=C(CCCl)Nc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2ccc(F)cc2N1
Temperature: 120 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To the solid of 3-chloro-N-(3-fluorophenyl)propanamide (3 g, 14.88 mmol) was added AlCl3 (6.3 g, 0.047 mmol) and maintained with an inert atmosphere of nitrogen with stirring for 5 h at 120° C. The reaction was then quenched with ice-water, extracted with ethyl acetate (3×50 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography with 4% ethyl acetate in petroleum ether to afford 7-fluoro-1,2,3,4-tetrahydroquinolin-2-one as a white solid (1.5 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(=O)N([Br:22])C(=O)C1.O>CN(C=O)C>[Br:22][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][CH2:12][C:13]#[N:14]
Reactant: COc1ccc(CCC#N)cc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)c(CCC#N)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1 g (5.3 mmoles) of 3-(3,4-dimethoxyphenyl)propanenitrile in 42 mL of DMF is cooled to 0° C. To the resulting solution there is added, little by little, 0.93 g of NBS (5.2 mmoles, 1 eq.). After stirring for 30 minutes at 0° C., the reaction mixture is brought back to ambient temperature and stirred for two hours. It is then hydrolysed using 170 mL of water and extracted twice with 130 mL of ethyl acetate. The organic phases are collected and then washed, first with saturated aqueous Na2S2O5 solution and then with water. After evaporating off the solvent under reduced pressure, 1.29 g of a colourless oil which crystallises into a white solid are obtained.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[NH:9][C:10]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24]Br>CC(O)=O>[C:18]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[NH:9][C:10]3[C:16]([Br:24])=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: Nc1ccc2nc(C(c3ccccc3)c3ccccc3)[nH]c2c1
Solvent: CC(=O)O
Product: Nc1ccc2nc(C(c3ccccc3)c3ccccc3)[nH]c2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 1.1 g (3.7 mmol) of 2-diphenylmethyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.07 ml (1.3 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (5% MeOH/EtOAC) to yield 0.42 g (1.1 mmol, 86%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.CN1CCOCC1.F[B-](F)(F)F.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C.[N:55]1([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C>[C:64]([O:63][C:61]([N:55]1[CH2:60][CH2:59][N:58]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:2]=2[Cl:1])=[O:13])[CH2:57][CH2:56]1)=[O:62])([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCCCOc1ccccc1-n1c(Cl)c(C(=O)O)c2ccccc21
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCOc1ccccc1-n1c(Cl)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of 200 mg (556 μmol) of the compound of step 5 in DMF (5 ml) and NMM (122 μl, 1.11 mmol) was added O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate (201 mg, 612 μmol), and the mixture was stirred at room temperature for 30 min. tert-Butyl 1-piperazinecarboxylate (114 mg, 612 μmol) was then added and the reaction mixture was stirred for 3 h. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (EA/HEP 2:5). 285 mg of the title compound were obtained.
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C[O-].[Na+].CO[C:14]1([CH2:20][CH:21]=[C:22]([C:25]#[N:26])[C:23]#[N:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH2:15]1>C(O)C>[CH:2]1([N:7]2[C:25]([NH2:26])=[C:22]([C:23]#[N:24])[C:21]([CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NNC1CCCC1
Reactant: COC1(CC=C(C#N)C#N)C=CC=CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1N
Yield: 25.8 %

Procedure:
A mixture of cyclopentyl hydrazine hydrochloride (1.4 g, 10.2 mmol), sodium methoxide (0.55 g, 10.2 mmol) and ethanol (30 ml) was heated to reflux and then (1-methoxyphenylethylidene)malononitrile (2.0 g, 10.2 mmol) in ethanol (15 ml) was added dropwise over 1 hour. The reaction mixture was refluxed for 6.5 hours and the solvent was removed in vacuo. The residue was partitioned between chloroform and water, the organic layer was separated and the aqueous layer was extracted with chloroform (3×75 ml). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 0.7 g (26%) of 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carbonitrile as white flakes, m.p. 180°-182° C. when recrystallized from ethyl acetate and dried for 18 hours at 90° C. in high vacuum.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[CH:10]([CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([C:23]([F:26])([F:24])[F:25])[CH:15]=2)[CH:10]([CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1cc(C(F)(F)F)cc2ccoc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1CN(Cc2ccccc2)CC=C1c1cc(C(F)(F)F)cc2ccoc12
Yield: 45.4 %

Procedure:
Beginning with 0.67 gm (1.72 mMol) 1-benzyl-3-methyl-4-hydroxy-4-(5-trifluoromethylbenzofur-7-yl)piperidine and 1.3 gm p-toluenesulfonic acid monohydrate, 0.29 gm (46%) of the desired compound were prepared essentially as described in EXAMPLE 3.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)=[CH:19][CH:20]=1
Reactant: O=C1Cc2cc(Cc3ccc([N+](=O)[O-])cc3)ccc2N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Cc2ccc3c(c2)CC(=O)N3)cc1
Reaction time: 2.5 h
Yield: 58 %

Procedure:
5-(4-Nitro-benzyl)-1,3-dihydro-indol-2-one (0.524 g, 1.94 mmols) was suspended in 35 ml of MeOH. 5% Pd/C (50 mg) was added to the flask which then was placed on a PARR apparatus. The flask was evacuated then charged with H2(g) (55 psi). This evacuation/H2(g) fill procedure was repeated 3 times (to degas the reaction mixture). The reaction vessel charged with H2(g) (55 psi) was shaken on the PARR apparatus for 2.5 hours after which the contents were filtered through celite. The organic solution was then concentrated in vacuo affording 5-(4-Amino-benzyl)-1,3-dihydro-indol-2-one at 58% yield (0.267 g, 1.12 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:25]([CH3:28])([O-:27])=[O:26]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:28]/[N+:25]([O-:27])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C=O)cc1OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 2.5 h

Procedure:
3-(Benzyloxy)-4-ethoxy benzaldehyde described in Production Example 15-2 (14.5 g, 56.4 mmol) was dissolved in acetic acid (45 mL), then ammonium acetate (5.22 g, 67.7 mmol) and nitromethane (7.5 mL, 138 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2.5 hours. The mixture was cooled to room temperature and the precipitate was collected by filteration and washed with ethanol to quantitatively obtain the title compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9](=[O:19])[C:8]1=[O:20])=[O:5])C.[OH-].[Na+]>C1COCC1.O>[C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9](=[O:19])[C:8]1=[O:20])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)cc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(Cl)cc(Cl)c21
Yield: 64.7 %

Procedure:
The ester of example 21 (34 mg, 0.107 mmol) was reacted with 0.1M NaOH (3.2 ml) in a mixture of THF (2.0 ml) and water (0,5 ml) for 26 h at 45° C. The solvent was removed in vacuo and the remanens was dissolved in water (1.0 ml), cooled in an ice bath and the pH was adjusted to 2.5 with 0.5 M hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 20 mg (65%) of the title compound. 1H-NMR (DMSO-d6):δ5.0 (s, 2H), 7.2 (d, 1H), 7.41 (d, 1H), 12.33 (s, 1H), 13.18 (br.s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[N+:12]([O-])([OH:14])=[O:13]>>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2=[N:9][C:8](=[O:10])[N:7]=[C:6]2[CH:11]=1
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=[N+]([O-])O
Product: Cc1cc2c(cc1[N+](=O)[O-])=NC(=O)N=2
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A mixture of 6-methyl-1,3-dihydro-benzoimidazol-2-one (0.30 g, 2.03 mmol) in 69% nitric acid (5 ml) was stirred over ice for 2 h. The yellow mixture was filtered and washed with water to give (22) as a bright yellow solid (0.39 g, 99.7%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].C([Li])CCC.O1C=CC=C1.[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[Cl-].[NH4+]>CCOCC.C(Cl)Cl.CCCCCC>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[OH:23]
Reactant: [Li]c1ccco1
Reactant: OCCCCCCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: OC(CCCCCl)c1ccco1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-furyllithium (prepared from 0.53 moles of n-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem., 27, 1216 (1962) in 350 ml of ether and ca. 200 ml of hexane at -78° is added a solution of 57.9 g of 5-chloropentanol (Chem. Abstr., 59. 7579F (1963)) in 80 ml of ether during 25 minutes. The mixture is warmed to 0°during 20 minutes, stirred at 0° for 15 minutes, and treated with 140 ml of saturated ammonium chloride. The ether phase is washed with water and brine, dried over magnesium sulfate and potassium carbonate mixture, and concentrated to give a liquid, pmr spectrum (CDCl3): δ 3.59 (triplet, CH2Cl2) and 4.70 (triplet, CH2CHOH).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.S[C:7]1[S:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=2[N:11]=1>>[Cl:4][C:7]1[S:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=2[N:11]=1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Reactant: O=S(=O)(Cl)Cl
Product: FC(F)(F)c1ccc2sc(Cl)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Sulfuryl chloride (9.09 g, 67.33 mmol) was added with stirring to 2-mercapto-5-(trifluoromethyl)benzothiazole (2.64 g, 11.22 mmol) over a period of 5 minutes. The reaction mixture was then allowed to stand for approximately 1 h. Ice water was added to the reaction mixture with stirring to decompose the excess of sulfuryl chloride, and the product was then extracted with ethyl acetate. The organic layer was washed with water (3×) and brine, dried over anhydrous Na2SO4 and concentrated. The resulting solid was dissolved in EtOAc and filtered though a short silica-gel column, eluting with EtOAc, to give 2-chloro-5-(trifluoromethyl)benzothiazole (2.50 g, 94%). LC-MS m/z 238.0 (MH+), ret. time 2.55 min; 1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, 1H), 8.38 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](Br)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:28][C:29]1[CH:34]=[C:33]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH:32]=[N:31][CH:30]=1
Reactant: Brc1cncc(Br)c1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(Br)c2)c1
Temperature: 80 °C

Procedure:
A mixture of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (2.00 g, 5.27 mmol), 3,5-dibromopyridine (4.37 g, 18.5 mmol) and Pd(dppf)Cl2—CH2Cl2 (0.215 g, 0.264 mmol) in 1,4-dioxane (26.4 mL, 0.2 M), and Na2CO3 (5.27 mL, 2.00 M) was purged with argon and heated to 80° C. for 4 hours. The reaction mixture was filtered through a CELITE plug and washed with dichloromethane. The eluent was diluted with water and extracted with dichloromethane (3×). The combined organic layers were concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford N-[3-(5-bromopyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine. MS APCI calc'd for C17H13BrF3N4 [M+H]+ 409 and 411. found 409 and 411.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][CH:10]2[C:15](=[O:16])[O:14]C(C)(C)[O:12][C:11]2=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([C:11]([OH:19])=[O:12])[C:15]([OH:16])=[O:14])=[CH:20][CH:21]=1)(=[O:3])=[O:4]
Reactant: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(CC(C(=O)O)C(=O)O)cc1

Procedure:
A solution of 5-(4-methylsulfonylbenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.50 g, 4.802 mmol, Intermediate 12: step a) and 3 M aqueous NaOH (16 mL) was heated in the microwave at 75 W for 20 minutes at 120° C. The aqueous mixture was extracted with EtOAc (1×). The aqueous layer was acidified to pH 1 with concentrated aqueous HCl and extracted with EtOAc (2×). The combined EtOAc extracts were washed with H2O, and brine, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a white solid.
Reaction SMILES: I[C:2]1[C:6](=[O:7])[S:5][C:4]2=[C:8](I)[C:9](=[O:11])[S:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])CCC>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.[Cu](I)I.C1(C)C=CC=CC=1>[CH2:23]([C:22]1[CH:21]=[CH:20][S:19][C:18]=1[C:2]1[C:6](=[O:7])[S:5][C:4]2=[C:8]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9](=[O:11])[S:10][C:3]=12)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCc1ccsc1[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1SC2=C(I)C(=O)SC2=C1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccsc1C1=C2SC(=O)C(c3sccc3CCCCCCCC)=C2SC1=O
Temperature: 90 °C
Yield: 46.2 %

Procedure:
The 3,6-diiodo-thieno[3,2-b]thiophene-2,5-dione (1.000 g; 2.370 mmol), tributyl-(3-octyl-thiophen-2-yl)-stannane (Bras, Jérôme; Guillerez, Stéphane; Pépin-Donat, Brigitte. Chem. Mater. 2000, 12, 2372-2384) (2.977 g; 5.213 mmol), PdCl2(PPh3)2 (166 mg; 0.237 mmol), copper Iodide (45 mg; 0.237 mmol) and toluene (100 cm3) is added in a 250 cm3 flask. The resulting mixture is carefully degassed for 30 minutes, and then heated at 90° C. for 16 h under nitrogen protection. Silica is added and the solvent removed in vacuo. The crude product is purified by column chromatography (eluent: petroleum ether 40-60:DCM; 70:30 ratio) to recover the pure product as a red powder (612 mg, Yield: 46%). NMR (1H, 300 MHz, CDCl3): δ 7.47 (d, J=5.1 Hz, 2H); 7.02 (d, J=5.1 Hz, 2H); 2.57 (t, J=7.8 Hz, 4H); 1.61 (m, 4H); 1.26 (m, 20H); 0.86 (t, J=6.7 Hz, 6H). NMR (13C, 75 MHz, CDCl3): δ 186.92; 154.77; 145.82; 129.91; 192.26; 129.05; 123.79; 32.01; 30.70; 30.06; 29.61; 29.52; 29.37; 22.81; 14.27.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[CH:11]=[C:10]([CH:12]=O)[CH:9]=[N:8][C:6]=2[N:7]=1.[NH2:15][C:16]1[CH:37]=[CH:36][C:19]([C:20]([NH:22][C@H:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])=[CH:18][CH:17]=1>C(O)(=O)C.[Ni]>[NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[CH:11]=[C:10]([CH2:12][NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][C@H:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])=[CH:36][CH:37]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2cc(C=O)cnc2n1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Agent: [Ni]
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Reaction time: 17 h

Procedure:
A solution of compound III (1.47 g, 5.90 mmol) in warm 70% acetic acid (59 ml) was cooled to 25° C., treated with diethyl p-aminobenzoyl-L-glutamate (2.28 g, 7.08 mmol) and hydrogenated in the presence of Raney nickel (6.3 g, weighed wet) at 25° C. and atmospheric pressure for 17 hours. The mixture was filtered and the catalyst was washed with 70% acetic acid (25 ml). The combined filtrate and wash was evaporated to dryness under high vacuum, and a solution of the residue in ethanol was filtered into 2 N Na2CO3 (60 ml). The mixture was stirred to give a homogeneous powder which was collected, washed with water and dried. A solution of the resultant powder in boiling ethanol (415 ml) was filtered hot and evaporated to dryness in vacuo. The residue was triturated with CHCl3 (85 ml), collected by filtration and the solid was washed with additional CHCl3 (40 ml). A suspension of the solid in boiling ethanol (140 ml) was stirred for 20 minutes and refrigerated. The product was collected by filtration and dried in vacuo (P2O5): yield 945 mg (32%), mp 262° C. (Kofler Heizbank). Mass spectrum, m/e 496 (M+1)+ ; λmax nm (ε×10-3); 0.1 N HCl --218 (42.4), 280 sh (19.3), 300 (22.0); pH 7--218 (36.4), 249 (20.2), 280 sh (22.3), 297 (23.6), 355 sh (6.10); 0.1 N NaOH --249 (22.0), 280 (23.8), 297 sh (22.5), 345 (7.23); 1H-NMR(DMSO-d6, 6% w/v), δ 1.18 m (CH3), 2.05 m (CH2CH2CO), 2.43 t (CH2CO), 4.08 m (CH2O), 4.32 m (CH2N, CHN), 6.31 s, 7.51 s (NH2), 6.67 d, 7.69 d (C6H4), 6.71 s (CH2NH), 8.25 d (CONH), 8.41 d (5 --CH, J=2.0 Hz), 8.66 d (7-CH, J=2.0 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]2[C:14]3[CH:20]=[CH:19][C:18]([C:21](OCC)=[O:22])=[CH:17][C:15]=3[N:16]=[C:10]2[CH2:9]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]2[C:14]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][C:15]=3[N:16]=[C:10]2[CH2:9]1
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCN(C)C1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCn2c(nc3cc(CO)ccc32)C1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
lithium aluminum hydride (0.21 g, 5.40 mmol) was suspended in tetrahydrofuran (15 ml), and under an ice cooling, a solution (5 ml) of ethyl 2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (0.70 g, 2.70 mmol) prepared in the Step 38-1-6 in tetrahydrofuran was slowly added dropwise to the suspension. After the mixture was stirred for 30 minutes under an ice cooling, and a saturated sodium bicarbonate solution was slowly added to the mixture under an ice cooling. Ethyl acetate was slowly added to the resulting mixture, and the precipitate was removed by filtration. The residue separated by filtration was carefully washed with chloroform. The washings and the filtrate were concentrated together. The concentrate was purified by silica gel column chromatography (chloroform:methanol=10:1 to 5:1) to give the title compound (0.56 g, 96%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[N:14]=[CH:13][C:12]4[N:18]([CH3:35])[C:19](=[N:32][C:33]#[N:34])[N:20]([C:21]5[CH:22]=[N:23][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:25][CH:26]=5)[C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].[C:40]([O-:43])(=O)[CH3:41].[K+]>C(OC(=O)C(CCC)CCC)(=O)C(CCC)CCC.O>[C:33]([N:32]=[C:19]1[N:18]([CH3:35])[C:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:8]([C:5]4[CH:4]=[C:3]([C:36]([F:38])([F:37])[F:39])[C:2]([NH:1][C:40](=[O:43])[CH:41]([CH2:6][CH2:5][CH3:8])[CH2:2][CH2:3][CH3:4])=[N:7][CH:6]=4)=[CH:9][C:10]=3[C:11]=2[N:20]1[C:21]1[CH:22]=[N:23][C:24]([C:27]([C:30]#[N:31])([CH3:28])[CH3:29])=[CH:25][CH:26]=1)#[N:34]
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(-c4cnc(N)c(C(F)(F)F)c4)ccc3ncc21
Reactant: CC(=O)[O-]
Agent: CCCC(CCC)C(=O)OC(=O)C(CCC)CCC
Agent: [K+]
Solvent: O
Product: CCCC(CCC)C(=O)Nc1ncc(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)nc2)c(=NC#N)n4C)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Example 5, 0.379 mmol) was stirred in valproic anhydride (5 mL). Potassium acetate (0.379 mmol) was added to it and the reaction was carried out at 110-115° C. for 2 h. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. Organic layer was concentrated, dried using anhydrous sodium sulfate and purified on silica gel column to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.32 (s, 1H), 9.08 (s, 1H), 8.63 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.28 (d, J=5.1 Hz, 1H), 8.18-8.15 (m, 1H), 8.01 (d, J=5.1 Hz, 1H), 7.06 (s, 1H), 3.94 (s, 3H), 1.77 (s, 3H), 1.56 (m, 2H), 1.35 (s, 6H), 1.23 (s, 1H), 0.91 (s, 6H); MS (m/z): 654.4 (M+1)+.