Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:12]2=3)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCS2
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
To a solution of methyl 4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (1.779 g, 4.84 mmol) in THF (12 mL) and water (6 mL) was added LiOH (0.6096 g). The reaction was allowed to stir at room temperature for 16 hours. LCMS analysis identified the product as the predominant component of the reaction mixture. The solvent was removed under reduced pressure. The resulting aqueous solution was acidified with 1N HCl to provide a white precipitate. The aqueous layer was extracted with DCM until the acid was no longer detected in the organic wash layer. The combined organics were washed with H2O and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by flash chromatography using a gradient elution of hexane with 0-95% ethyl acetate doped with 1% AcOH. The product, 4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (1.108 g, 3.14 mmol, 65% yield), was isolated as off-white solid. LCMS (+ESI) m/z=354.0 [M+H]+.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:14]([OH:16])=O)[CH:11]([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:40][CH:39]=1>CN(C=O)C.CO.C(Cl)CCl>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([CH:44]2[CH2:45][CH2:46][N:47]([C:14](=[O:16])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]([CH3:12])[CH3:13])[CH2:48][CH2:49]2)=[CH:40][CH:39]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A reaction vessel was charged with benzoyl-DL-valine (24 mg), HOBt (16 mg), DIEA (57 μL), 4-(4-chlorophenyl)piperidine hydrochloride (28 mg) and EDC (23 mg) in DMF (1.5 mL) and then agitated at rt. for 16 h. At the conclusion of this period, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 208. MS found: (M+H)+=399.
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Cl:42][C:43]1[CH:49]=[C:48]([Cl:50])[C:47]([O:51][CH3:52])=[CH:46][C:44]=1[NH2:45]>>[Cl:42][C:43]1[CH:49]=[C:48]([Cl:50])[C:47]([O:51][CH3:52])=[CH:46][C:44]=1[NH:45][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=2)[N:30]=[CH:29][N:28]=1
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3cc(OC)c(Cl)cc3Cl)c2cc1N

Procedure:
Starting material: N4-(2,4-dichloro-5-methoxyphenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting material was 4-chloro-7-methoxy-6-nitro-quinazoline and 2,4-dichloro-5-methoxyaniline; other starting materials were prepared as example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[N+:30]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].CO.C1COCC1>[Fe].O>[NH2:30][C:15]1[CH:16]=[C:17]([NH:20][C:21](=[O:29])[C:22]2[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=2)[CH:18]=[CH:19][C:14]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:34][CH:33]=1
Reactant: O=C(Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(NC(=O)c2ccc(Br)cc2)ccc1Oc1ccc(OCc2ccccc2)cc1
Yield: 72.9 %

Procedure:
The product from Example 247b (1.18 g, 2.27 mmol), iron powder (0.51 g, 9.1 mmol) and ammonium chloride (0.14 g, 2.5 mmol) in a methanol (10 ml), THF (10 ml) and water (5 mL) solution was heated at reflux for 1.5 hr. The resultant mixture was filtered, rinsed with hot methanol (50 ml) and concentrated under vacuum to an oily residue. The residue was diluted with ethyl acetate (100 ml) and washed with water and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and the organic solvent was removed under vacuum providing the title compound (0.81 g, 73%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12]>>[OH:9][CH:5]([CH:6]([CH3:8])[CH3:7])[C:2]([CH3:10])([CH3:1])[CH2:3][O:4][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=1[C:16]#[N:17]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)C(O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 215c from 2,2,4-trimethylpentane-1,3-diol and 2,6-dinitrobenzonitrile in 90% yield. MS 293 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[N:10]=[C:9]1[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1N(CC2C=CC(Cl)=CC=2)C2C(=O)N([CH2:47][CH2:48][CH2:49][O:50][CH:51]3[CH2:56][CH2:55][CH2:54][CH2:53][O:52]3)C(=O)N(C)C=2N=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:47][CH2:48][CH2:49][O:50][CH:51]3[CH2:56][CH2:55][CH2:54][CH2:53][O:52]3)[C:13](=[O:18])[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:11]=2[N:10]=[C:9]1[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (5 g, 12.32 mmol) in DMF (30 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (3.60 g, 16.22 mmol, intermediate 14 step 1), followed by potassium carbonate (3.4 g, 24.64 mmol). The mixture was stirred at 65° C. overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (6.3 g, 93.3% yield) as yellow oil. LCMS retention time 3.574 min; LCMS MNa+ 571.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[CH:10]=[CH:11][CH:12]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(F)c(OCC(=O)c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)c(OC[C@@H](O)c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-CBS reagent (46.5 mL, 1M in toluene) was added to a THF solution (200 mL) of borane-diethylaniline complex (15.16 g) were stirred together 15 min at room temperature. 3-{2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-ethoxy}-4-fluoro-benzonitrile (20 g) in 600 mL of dry THF was then added through an addition funnel at rt over 20 minutes. The mixture was stirred for 15 minutes and then was quenched by slow addition of 60 mL MeOH. After gas evolution ceased, the mixture was evaporated and water was added to the residue and extracted with ethyl acetate. Ethyl acetate layer separated and washed with water, brine, dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column (DCM; 10% EtOAc in DCM) to get pure product. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.45 (d, 1H), 7.15-7.35 (m, 4H), 7.09 (t, 1H), 7.04 (d, 1H), 6.92 (m, 1H), 5.15 (m, 1H), 5.04 (s, 2H), 4.10 (m, 2H), 2.63 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.N1C=CC=CC=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].Cl>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:17][C:18]([OH:20])=[O:19]
Reactant: Cc1ccccc1C=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C=CC(=O)O
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a stirred solution of o-methylbenzaldehyde (50 g, 417 mmol) in pyridine (2 equiv, 65 mL) was added malonic acid (86.6 g, 834 mmol) and the mixture was refluxed for 4-5 h. The reaction mixture was then poured into ice-water followed by 1N HCl. The white solid precipitated out was filtered, washed with water and concentrated under high vacuum for 3-4 h to get the desired product (57 g, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:26]2[NH:27][C:23](=[CH:24][CH:25]=2)[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:21]2[N:34]=[C:18]([CH:19]=[CH:20]2)[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[C:16]2[NH:41][C:13]([CH:14]=[CH:15]2)=[C:12]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C:11]2=[N:48][C:8]=1[CH:9]=[CH:10]2.[C:49]12[CH:72]=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=C[CH:50]=2.CO.C(Cl)(Cl)Cl>C(Br)C=C>[CH2:7]([C:33]1[C:28]([C:22]2[C:23]3[NH:27][C:26](=[CH:25][CH:24]=3)[C:7]([C:2]3[C:3]([CH2:6][CH:5]=[CH2:4])=[CH:4][CH:5]=[CH:6][N:1]=3)=[C:8]3[N:48]=[C:11]([CH:10]=[CH:9]3)[C:12]([C:42]3[C:47]([CH2:72][CH:49]=[CH2:50])=[CH:46][CH:45]=[CH:44][N:43]=3)=[C:13]3[NH:41][C:16]([CH:15]=[CH:14]3)=[C:17]([C:35]3[C:40]([CH2:10][CH:9]=[CH2:8])=[CH:39][CH:38]=[CH:37][N:36]=3)[C:18]3=[N:34][C:21]=2[CH:20]=[CH:19]3)=[N:29][CH:30]=[CH:31][CH:32]=1)[CH:2]=[CH2:3]
Reactant: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Reactant: C1=Cc2nc1c(-c1ccccn1)c1ccc([nH]1)c(-c1ccccn1)c1nc(c(-c3ccccn3)c3ccc([nH]3)c2-c2ccccn2)C=C1
Solvent: CO
Solvent: C=CCBr
Solvent: ClC(Cl)Cl
Product: C=CCc1cccnc1-c1c2nc(c(-c3ncccc3CC=C)c3ccc([nH]3)c(-c3ncccc3CC=C)c3nc(c(-c4ncccc4CC=C)c4ccc1[nH]4)C=C3)C=C2
Temperature: 100 °C
Yield: 78 %

Procedure:
In an oven-dried flask under argon, 100 mg tetrakis(2-pyridyl)porphyrin (2-PyP) was dissolved in 5 mL allyl bromide, and reaction was heated at 100° C. for 16 hours. The reaction mixture was heated at 100° C. for 8 hours. Two methods were used to monitor the completion of the reaction. First, the shift of the porphyrin Soret band from λmax=412 nm (methanol) to λmax=418 nm (methanol) was monitored. A second method involved partition of an aliquot of the reaction mixture between H2O and CHCl3 whereby a complete reaction showed no color in the CHCl3 layer. Upon completion of the reaction, the allyl bromide was distilled off under high vacuum, and the residue was triturated with ethyl ether (Et2O). Chromatography was performed on Sephadex LH-20 (column dimensions were 2×20 cm) using methanol as the eluent and fractions that showed porphyrin with λmax=418 nm were retained. Compound VIII was produced as a shiny purple solid, in 78% yield. Absorbance data included the following: UV-vis: λmax (nm) (log10εo) 418(5.29) 512 (4.50) 587(4.32). Electrospray mass spectrometry (ES-MS) showed a molecular ion at 782 (M-4 Br).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9]([F:16])=[N:10][C:11]([F:15])=[N:12][C:13]=1F.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:7][C:8]1[C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:12][C:11]([F:15])=[N:10][C:9]=1[F:16]
Reactant: Fc1nc(F)c(Cl)c(F)n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1nc(F)c(Cl)c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Morpholine (0.774 mg) was added to a solution of 5-chloro-2,4,6-trifluoropyrimidine (1.5 g), N,N-diisopropylethylamine (1.15 g) in 1,4-dioxane (30 ml) and stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water, the organic layer dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 8% ethyl acetate in isohexane. Yield 0.88 g
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].II>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[OH:17])[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(c1=O)C(=O)CCC2
Agent: II
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2cccc(O)c2c1=O
Yield: 44.1 %

Procedure:
To a solution of 4,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (1.6 g, 6.8 mmol) in ethanol (100 mL) was added iodine (4.8 g, 19 mmol). The mixture was refluxed for 19 h and then concentrated under reduced pressure. The resulting solid was washed with ethyl acetate, water and acetone, and then recrystallized from DMF to give 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([OH:34])=O)=[CH:31][C:26]=2[O:25][N:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.S(Cl)([Cl:44])=O>ClCCl>[Cl:44][C:32]([C:30]1[CH:29]=[CH:28][C:27]2[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:24][O:25][C:26]=2[CH:31]=1)=[O:34]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(=O)O)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(=O)Cl)ccc12

Procedure:
To a solution of 3-(2-(1(S)-(tert-butoxycarbonylamino)-2-(pyridin-2-yl)ethyl) -phenyl)benzo[d]isoxazole-6-carboxylic acid (Compound 18a) (45 mg) dissolved in dry dichloromethane (2 mL) under nitrogen, cooled with ice bath, was added triethylamine (127 μL) then thionyl chloride (35.5 μL). After 10 min the solvents were removed under reduced pressure to give the title product.
Reaction SMILES: C(=[N:14][NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([C:23]1[N:27](COCC2C=CC=CC=2)[C:26]2[CH:37]=[CH:38][CH:39]=[CH:40][C:25]=2[N:24]=1)=O)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CCCCCCC>[NH:15]1[C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([C:23]2[NH:27][C:26]3[CH:37]=[CH:38][CH:39]=[CH:40][C:25]=3[N:24]=2)=[N:14]1
Reactant: O=C(c1sccc1NN=C(c1ccccc1)c1ccccc1)c1nc2ccccc2n1COCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCCCCCC
Product: c1ccc2[nH]c(-c3n[nH]c4ccsc34)nc2c1
Temperature: 75 °C

Procedure:
A mixture of [3-(N′-benzhydrylidene-hydrazino)-thiophen-2-yl]-(1-benzyloxymethyl-1H-benzoimidazol-2-yl)-methanone (300 mg, 0.553 mmol, Example 1D), concentrated hydrochloric acid (4 mL), and ethanol (12 mL) is heated at 75° C. for 260 minutes. The reaction is allowed to cool to ambient temperature, diluted with water (40 mL), and basified with 5% aqueous potassium carbonate. The mixture is extracted with ethyl acetate and the combined extracts washed with water and brine successively. The organic layer is dried over potassium carbonate and concentrated under reduced pressure to give a brown solid. The solid is chromatographed on silica. Step gradient elution with 70% ethyl acetate/heptane, 80% ethyl acetate/heptane, and 90% ethyl acetate/heptane provided an orange solid. Trituration with ethyl acetate/heptane gave 2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-benzoimidazole as a beige powder: TLC Rƒ0.28 (silica, 75% ethyl acetate/heptane); LC/MS: (M+H 241.0, RT=2.15 minutes); 1H NMR [(CD3)2SO), 300 MHz]: δ 13.56 (s, 1H), 12.94 (2, 1h), 7.78 (d, 1H, 5.3 Hz), 7.69 (d, 1H, 7.3 Hz), 7.48 (d, 1H, 7.0 Hz), 7.22-7.15 (m, 3H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:26][CH2:25][C:24]2[C:19](=CC=C[CH:23]=2)[CH2:18]1.Cl.CC1N(C2N=CC=CN=2)N=CC=1/C=C/CN1CCC2C(=CC=CC=2)C1.Cl.CC1CCNCC=1>>[ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:26][CH2:25][C:24]([CH3:23])=[CH:19][CH2:18]1
Reactant: Cc1c(C(=O)CCN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: CC1=CCNCC1
Agent: Cc1c(/C=C/CN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cl
Product: CC1=CCN(C/C=C/c2cnn(-c3ncccn3)c2C)CC1

Procedure:
The procedures of Example 6 (1) and (2) were repeated but substituting the 1,2,3,4-tetrahydroisoquinoline hydrochloride employed in Example 6 (1) by 4-methyl-1,2,5,6-tetrahydropyridine hydrochloride. After the completion of the post treatment, the title compound was obtained.
Reaction SMILES: [CH:1]([C:4]([CH:6]([CH3:8])[CH3:7])=[O:5])([CH3:3])[CH3:2].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2>>[CH:1]([C:4]([CH:6]([CH3:8])[CH3:7])([OH:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)C(C)C
Reactant: ClCCCCCC1CC2C=CC1C2
Product: CC(C)C(O)(CCCCCC1CC2C=CC1C2)C(C)C
Yield: 85 %

Procedure:
1,1-Diisopropyl-6-(5-norbornen-2-yl)hexanol (yield: 85%) was obtained in the same manner as in Synthesis Example 1, except that diisopropyl ketone and 1-chloro-5-(5-norbornen-2-yl)pentane were used in place of acetone and 1-chloro-4-(5-norbornen-2-yl)butane, respectively.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH2:54][CH:55]=[CH2:56])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([O:59][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:67])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH2:54][CH:55]=[CH2:56])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([OH:59])[CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-azido-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (17.5 mg) in acetonitrile (1 ml) was added a solution of 2% HF in aqueous acetonitrile (100 μl), and the mixture stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (10 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(N)(=[S:28])C.Cl.O1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:24](=[S:28])[NH2:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nc(-c2nc(C(N)=S)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 102.5 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (665 mg) and thioacetamide (451 mg) in DMF (3.2 ml) was added a 4N hydrogen chloride solution of dioxane (3.2 ml) and the mixture was stirred at 100-105° C. for 2 hours. Water (65 ml) was added to the mixture to yield a precipitate. The precipitate was collected by filtration, subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give a solid. The solid triturated with acetone and collected by filtration to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbothioamide as a solid (417 mg).
Reaction SMILES: C(C1NC2C(C=1)=[C:9]([O:12]C)[CH:8]=[CH:7]C=2)C.C([Li])(CC)C.[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1[CH3:35])=[O:25])([CH3:22])([CH3:21])[CH3:20].CON(C)C(=O)CC>C1CCCCC1.C1COCC1>[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1[CH2:35][C:9](=[O:12])[CH2:8][CH3:7])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Reactant: CCc1cc2c(OC)cccc2[nH]1
Agent: CCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
2-Ethyl-4-methoxy-1H-indole. A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature had cooled to -60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole.