Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH3:23])=[C:9]2[CH3:24])=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[CH3:24][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)=[CH:3][CH:4]=2)[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:11][C:10]=1[CH3:23]
Reactant: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(Br)cc2)c1C
Reactant: OB(O)c1ccoc1
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(-c3ccoc3)cc2)c1C

Procedure:
The title compound was prepared according to the procedure of Example 35 using 1-(4-bromophenyl)-2,3-dimethyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole and 3-furanboronic acid instead of 2-furanboronic acid in step 4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH:16]([CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>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>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[CH:15][CH:16]([CH3:27])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=4)=[CH:6][CH:7]=3)=[CH:40][CH:41]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CC(C)Cc1ccc(C(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CC(C)Cc4ccc(C(C)C)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and the following starting materials: 5-(4-bromo-phenyl)-4-[4-(4-isopropyl-phenyl)-3-methyl-but-1-enyl]-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[C:8]3[NH:21][C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][C:27]=4[C:7]3=[CH:6][C:5]2=1.[Br:29]Br.C(Cl)Cl>CN(C=O)C>[Br:29][C:6]1[C:7]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][C:8]=2[C:9]([O:15][CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][C:4]=3[C:5]=12
Reactant: BrBr
Reactant: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(Br)c2c1[nH]c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 2-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (213.9 mg, 0.5638 mmol) in DMF (20 mL) at 0° C. was added Br2 in CH2Cl2 (50 mg/mL, 1.982 mL, 0.6201 mmol). The reaction was warmed to room temperature and stirred for two hours. DMF was removed via vacuum pump. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aq. NaCO3. The organic layers was concentrated and subjected to flash chromatography to provide the title compound (188.4 mg, 73%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.89 (br s, 2 H), 8.39 (dd, J=10.0, 2.4 Hz, 2 H), 7.55 (dd, J=8.8, 4.4 Hz, 2 H), 7.31 (td, J=8.8, 2.4 Hz, 2 H), 4.34 (t, J=5.2 Hz, 2 H), 2.74 (t, J=5.6 Hz, 2 H), 2.36 (s, 6 H); MS (ESI) m/z 456.1 (M−H)−; MS (ESI) m/z 458.0 (M+H)+
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C:21]2([CH:31]=O)[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:33][C:34]([F:48])([F:47])[C:35]1[CH:36]=[C:37]([CH2:45][NH2:46])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1.C(=O)([O-])O.[Na+]>ClC(Cl)C>[C:15]1([C:21]2([CH2:31][NH:46][CH2:45][C:37]3[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=[C:35]([C:34]([F:33])([F:47])[F:48])[CH:36]=3)[CH2:30][CH2:29][C:24]3([O:25][CH2:26][CH2:27][O:28]3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CC1(c2ccccc2)CCC2(CC1)OCCO2
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: FC(F)(F)c1cc(CNCC2(c3ccccc3)CCC3(CC2)OCCO3)cc(C(F)(F)F)c1
Yield: 47 %

Procedure:
Sodium triacetoxyborohydride (4.77 g, 22.5 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro[4.5]decane-8-carboxaldehyde (J. Med. Chem. 1975, 18, 593-599). (1.1 g, 4.5 mmol) and 3,5-bis(trifluoromethyl)benzenemethanamine (1.1 g, 4.5 mmol) in dichloroethane (50 mL) and the mixture was stirred at room temperature overnight. The mixture was poured into saturated aqueous sodium hydrogen carbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25), to give the title compound as a yellow oil (1.0 g, 47%). m/z (ES+) 473 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[OH-:12].[Na+].[Cl-].[Na+]>O.[Cl-].[Cl-].[Zn+2]>[CH2:8]([C:7]1[C:5](=[O:6])[CH2:4][CH:3]([OH:12])[C:2]=1[CH3:1])[CH2:9][CH3:10]
Reactant: [OH-]
Reactant: Cc1ccc(CCCCO)o1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: CCCC1=C(C)C(O)CC1=O

Procedure:
In a reaction vessel, 5-methyl-2-furylpropylcarbinol (1 g) was charged, and a solution of ZnCl2 (0.9 g) in water (40 ml) was added. The temperature was elevated up to 100° C. to reflux, and several drops of an aqueous 0.1N NaOH solution were added thereto to adjust the pH value to 4.5. By further addition of the same NaOH solution (0.3 ml) thereto, the pH value was not changed but remained at 4.5. The mixture was stirred under reflux for 11 hours, whereby the pH value became 4.2. After cooling, sodium chloride (12 g) was added thereto, and the mixture was extracted with toluene (30 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove toluene, and the resultant residue was subjected to chromatography with silica gel (10 g) and a mixture of ethyl acetate-n-hexane (1:2 by volume) as the developing solvent to obtain 2-propyl-3-methyl-4-hydroxy-2-cyclopentenone (0.57 g). Yield, 57%.
Reaction SMILES: [OH:1][CH2:2][C@:3]([NH:15]C(=O)OC(C)(C)C)([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH3:4].[Cl:23]S([N:27]=[C:28]=[O:29])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[ClH:23].[C:28](=[O:29])([O:1][CH2:2][C@:3]([NH2:15])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)[CH3:4])[NH2:27]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)c1cccc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C[C@](N)(COC(N)=O)c1cccc(C(F)(F)F)c1
Product: Cl
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
A solution of 520 mg (1.63 mmol) of the compound from Example 70A in 10 ml of acetonitrile was cooled to −15° C. and admixed with 198 μl (2.28 mmol) of chlorosulphonyl isocyanate. After 10 min, 18 ml of water were added and the mixture was heated at 60° C. overnight. After cooling to RT, the solution was rendered alkaline by addition of saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvents on a rotary evaporator. For complete deprotection of the amino group, the residue was admixed with 5 ml of a 4M solution of hydrogen chloride in dioxane, and this mixture was stirred at RT for 5 min and concentrated on a rotary evaporator. Drying of the residue in an HV gave the title compound (440 mg, 90% of theory).
Reaction SMILES: [CH2:1]([N:5]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:24])[CH:12]2[CH:7]([CH2:8][CH:9]=[CH:10][CH2:11]2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36]C(C)(C)C)=[O:35]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:5]1[C:6](=[O:25])[CH:7]2[CH:12]([CH2:11][CH:10]=[CH:9][CH2:8]2)[C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:16]=2[CH3:24])=[N:14]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCN1N=C(c2c(C)[nH]c3ccccc23)C2CC=CCC2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN1N=C(c2c(C)n(CC(=O)O)c3ccccc23)C2CC=CCC2C1=O
Temperature: 75 °C

Procedure:
The product of step b) was dissolved in DMF (4 mL) and treated with K2CO3 (0.7 mmol, 97 mg) and t-butyl bromoacetate (0.5 mmol, 74 uL). After heating at 75° C. for 2 h, the reaction was cooled, diluted with EtOAc (10 mL) and washed 3× water. The organic solution was concentrated to dryness and treated with 4 mL TFA for 1.5 h. The reaction was concentrated and the title compound was purified by preparative LCMS. 1H NMR (DMSO-d6) δ 7.76 (d, J=8.1 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.09-6.99 (m, 2H), 5.70 (d, J=10.8 Hz, 1H), 5.63 (d, J=10.8 Hz, 1H), 3.91 (dt, J=6.9, 13.2 Hz, 1H), 3.62 (dt, J=6.6, 13.2 Hz, 1H), 3.36 (quint., J=5.7 Hz, 1H), 2.96 (t, J=5.1 Hz, 1H), 2.79-2.71 (m, 1H), 2.35-1.94 (m, 4H), 1.64 (quint., J=7.1 Hz, 2H), 1.31 (sext., J=7.5 Hz, 1H), 0.91 (t, J=7.2 Hz, 3H); MS: ESI (negative): 392 (M−H).
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.Cl.[C:37]1([C@H:47]([NH2:49])[CH3:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:14]([NH:13][C@@H:12]([C:11]([NH:49][C@@H:47]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)[CH3:48])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1cccc2ccccc12
Yield: 136.2 %

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine-o-nitrophenyl ester (5.2 g; 10.6 mmol; see Example 4(a) above), (R)-1-(1-naphthyl)ethylamine hydrochloride (2.0 g; 11.7 mmol), and CH2Cl2 (150 mL), 48 hours reaction time. The resultant yellow solution was concentrated to afford the crude sub-title compound as a solid (7.5 g) which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(NS(=O)(=O)c2ccc(Cl)cc2)C(C)C)cc1
Yield: 38.8 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methylbutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (665 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.9 ml) and 1-methyl-2-chloropyridinium iodide (1.05 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-methylbutanamide (542 mg).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH3:15])[N:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[CH2:7][CH2:6]1)[CH3:3].S(O)(O)(=O)=O.C[NH:27]C(=N)O.[C:31](=[O:34])([O-])[O-].[K+].[K+]>C(#N)C>[CH3:31][O:34][C:3]1[N:2]=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][N:11]([CH3:15])[C:12]=3[C:13]=2[N:27]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCC(=CN(C)C)C2=O
Reactant: O=C([O-])[O-]
Reactant: CNC(=N)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(OC)nc1-2
Yield: 81.9 %

Procedure:
2.0 g (7.2 mmol) of ethyl 6-[(dimethylamino)methylene]-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate were dissolved in 200 mL of acetonitrile and 17.4 g (70.6 mmol) of methylisourea sulfate and 10.0 g (72.4 mmol) of potassium carbonate were added. The reaction mixture was stirred at reflux for 16 hours. The solvent was then evaporated, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated. After a chromatography on a silica gel column (eluant dichloromethane) 1.7 g of product were obtained (86% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>C(O)CCC>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][N:6]=2)[NH:19][N:18]=1
Reactant: Fc1ccccc1C#Cc1nccnc1Cl
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Fc1ccccc1Cc1n[nH]c2nccnc12

Procedure:
A solution of 550 mg (2.36 mmol) of 2-chloro-3-[(2-fluorophenyl)ethynyl]pyrazine from example 13A and 592 mg (11.8 mmol) of hydrazine hydrate in 12 ml of n-butanol is heated in a microwave at 140° C. for 30 min. The solution is then concentrated in vacuo, and the residue is purified by preparative HPLC. 150 mg (26% of theory) of the desired compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N+:11]([O-])([O-:13])=[O:12].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(C=O)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-Methoxy-benzaldehyde (1 g, 7.34 mmol) was added to a mixture of ammonium nitrate (0.58 g, 7.34 mmol) and trifluoroacetic anhydride (3.56 mL, 25.69 mmol), which was cooled to 0° C. The reaction mixture was stirred at 0° C. for 15 min and then allowed to stir at room temperature for about 7 h. Ice was added and stirred for 30 min. The solid obtained was filtered, washed with cold water (3×5 mL) and dried.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccsc1
Product: O=C(O)CCC(=O)c1cccs1

Procedure:
Thiophene (a) is reacted with succinic anhydride (c) under Friedel-Crafts reaction conditions to afford 4-(2-thienyl)-4-oxobutyric acid (XII). Substitution of benzene (b) in the above reaction affords 4-phenyl-4-oxobutyric acid (XVII). ##STR18## The oxobutyric acids of formulas (XII) and (XVII) obtained in Step 1 above, are reacted with a suitable 1,2-dithiol (d), R3 and R4 are each either hydrogen or methyl, in an aromatic solvent such as benzene, toluene or xylene, in the presence of catalytic amounts of p-toluenesulfonic acid at a temperature range of 25° C. to 120° C. and, preferably, from 75° C. to 110° C. while azeotroping the water formed in the reaction. Alternatively, the reaction is conducted in a C2 -C5 alkanoic acid, preferably, acetic acid in the presence of an acid catalyst such as boron trifluoride/methanol, boron trifluoride/ether, ZnCl2 /Na2SO4, HCl/ether, and the like, at the temperature range specified above, to afford 2-(2-thienyl)-1,3-dithiolane-propionic acid (XIII) and 2-phenyl-1,3-dithiolane-2-propionic acid (XVIII), respectively. R3 and R4 are as hereinabove defined. ##STR19## The dithiolane propionic acids of formulae (IIIa) and (IIIb) are converted to the corresponding acid chlorides of formulae (XIV) and (XIX) with oxalyl chloride or thionyl chloride (with a small amount of DMF added if desired) in an inert anhydrous solvent selected from the group consisting of benzene, toluene, xylene, chlorobenzene, at a temperature range of about 0° C. to 30° C. and preferably 15° C. to 30° C. ##STR20##
Reaction SMILES: [N:1]1(C(=O)C)[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[OH-].[Na+]>O1CCCC1.CO.O>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: CC(=O)n1ncc2ccncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: c1cc2cn[nH]c2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-pyrazolo[3,4-c]pyridin-1-yl-ethanone (20.2 mg, 0.17 mmol, 1 equiv) in tetrahydrofuran (2 mL) and methanol (0.5 mL) was added sodium hydroxide aqueous solution (2M, 0.25 mL). The reaction solution was stirred at room temperature for 1 hr and then concentrated in vacuo to provide a crude residue. The crude residue was diluted with water (20 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 1H-pyrazolo[3,4-c]pyridine as white powder, which used without further purification: LCMS (ES) M+H 120.3, Rf 0.22 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)([O-:27])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[N+]([O-])c1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Yield: 4.5 %

Procedure:
The title compound (0.005 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using 3-nitrobenzyl bromide (0.09 g) in place of benzyl chloride and Cs2CO3 (0.2 g) in place of NaH. MS (ESI): exact mass calculated for C20H19ClN4O2, 382.12; found, m/z 383.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.07-8.05 (m, 1H), 7.91-7.87 (m, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.44-7.38 (m, 3H), 7.36-7.33 (m, 2H), 5.41 (s, 2H), 2.88-2.85 (m, 4H), 2.82-2.79 (m, 2H), 2.73-2.71 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][NH:13][CH3:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: CNCc1cn(C)c2cc(F)ccc12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2cc(F)ccc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 50.1 %

Procedure:
According to the procedure of Example 24, except substituting 6-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.11 g, 0.59 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.098 g, 0.59 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.1 g, 27%) was prepared as a white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:6]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)Oc1ccc(-c2ccc(CCNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Yield: 26 %

Procedure:
Ethyl 2-{4-[2-(2-methoxy-5-chloro-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(2-methoxy-5-chlorobenzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-propionate analogous to Example 1. Yield: 26% of theory; m.p. <20° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[CH:4]1.C1([OH:21])C=CC=CC=1>C(OCC)C>[ClH:1].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13](=[NH:14])[OH:21])=[CH:4]1
Reactant: Oc1ccccc1
Reactant: Cn1cc(CC#N)c2ccccc21
Agent: Cl
Solvent: CCOCC
Product: Cn1cc(CC(=N)O)c2ccccc21
Reaction time: 96 h
Yield: 30 %

Procedure:
Hydrogen chloride was bubbled through a solution of 3 g (176 mmol) of 1-methylindole-3-acetonitrile and 8.28 g (88 mmol) of phenol in 70 ml of dry diethyl ether for 2 hours and the resulting solution was left to stand for 4 days. The solvent was removed under reduced pressure. The residual gum was triturated with diethyl ether to give 1.4 g (30%) of 1-methyl3-indoleacetimidate hydrochloride in the form of a purple solid of melting point 119° C.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1C=CC=C1CC(O)=O.[C:24]([O:27]CC)(=O)[CH3:25]>C(Cl)Cl>[C:24]([S:15][CH2:14][CH:10]([CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([OH:13])=[O:12])(=[O:27])[CH3:25]
Reactant: O=C(O)Cc1cccs1
Reactant: C=C(CSCc1ccccc1)C(=O)O
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)SCC(CSCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-benzylsulfanylmethyl-acrylic acid (0.208 g) in methylene chloride (2.5 mL) was treated with thiolacetic acid and stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and then washed twice with water and once with saturated aqueous sodium chloride. After drying over magnesium sulfate the solvent was removed by rotary evaporation and the residue chromatographed on silica gel eluting with an ethyl acetate/hexane/acetic acid mixture to produce 3-acetylsulfanyl-2-benzylsulfanylmethyl-propionic acid (0.208 g).