Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:9]1[C:4]([Cl:3])=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[Cl:10]
Reactant: CC(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c(Br)c(Cl)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
21.3 ml of bromine diluted in 82 ml of acetic acid are added over 6 hours to 84.86 g of N-(3,5-dichlorophenyl)acetamide and 34 g of sodium acetate in 420 ml of acetic acid. After 12 hours at room temperature, the reaction mixture is heated for 5 hours at 50° C. The solvents are evaporated off under reduced pressure. The residue obtained is recrystallized from isopropanol; m.p.=224° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]#[N:15].O>C(OCC)(=O)C.C(O)C>[C:2]([CH:13]([C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[Cl:5])[C:14]#[N:15])(=[O:1])[CH3:3]
Reactant: CC[O-]
Reactant: N#CCc1ccc(F)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)C(C#N)c1ccc(F)cc1Cl
Temperature: 70 °C
Yield: 69.9 %

Procedure:
A suspension of dry, solid sodium ethoxide (Aldrich, 10.2 g, 150 mmol) in a mixture of xylenes (60 mL) and anhydrous ethanol (25 mL) was stirred at 70° C., and a solution of 2-chloro-4-fluorobenzeneacetonitrile (16.96 g, 100 mmol) in a mixture of ethyl acetate (30 mL) and ethanol (5 mL) was added dropwise to the hot reaction mixture over 20 minutes. The reaction mixture was heated at 75-78° C. for 3 h and then allowed to cool. Water (50 mL) was added to dissolve solids. The mixture was extracted once with ethyl acetate, and the extract was discarded. The aqueous phase was acidified to pH 2 by addition of 1 N aqueous hydrochloric acid, and then extracted with ethyl acetate (50 mL). The ethyl acetate phase was dried (MgSO4) and evaporated to provide the intermediate product α-acetyl-2-chloro-4-fluorobenzeneacetonitrile as a solid (14.8 g).
Reaction SMILES: I[C:2]1[C:3]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:15][C:16]1[CH:17]=[N:18][NH:19][CH:20]=1.[C@@H]1(N)CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C1(C)C=CC=CC=1>[Br:15][C:16]1[CH:17]=[N:18][N:19]([C:2]2[C:3]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1I
Reactant: Brc1cn[nH]c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1ncccc1-n1cc(Br)cn1
Temperature: 110 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a mixture of N-(3-iodo-pyridin-2-yl)-2,2-dimethyl-propionamide (380 mg, 1.2 mmol) described in Manufacturing Example 39-1-2 and toluene (10 mL) were added 4-bromopyrazole (160 mg, 1.1 mmol), copper (I) iodide (11 mg, 0.056 mmol), trans-1,2-cyclohexanediamine (26 mg, 0.22 mmol) and potassium carbonate (340 mg, 2.5 mmol) at room temperature, which was stirred overnight at 110° C. The reaction mixture was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (190 mg, 52%).
Reaction SMILES: [Na+].[NH2:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([O-:9])=[O:8].[CH3:13]O>Cl>[NH2:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([O:9][CH3:13])=[O:8]
Reactant: CO
Reactant: Nc1ccc(C(=O)[O-])c(O)c1
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccc(N)cc1O
Reaction time: 0.5 h

Procedure:
To a solution of 25 g (118.5 mmol) of 4-aminosalicylic acid sodium salt in 250 ml of methanol is bubbled in anhydrous HCl gas at room temperature. Addition of HCl gas is continued for 30 minutes. Excess methanol is removed in vacuo and the residue taken up in ethyl acetate and washed with saturated aqueous NaHCO . The organic layer is dried over MgSO4, filtered and concentrated, giving methyl 4aminosalicylate which is used directly in the next step.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 73 as a pale yellowish solid; mp 173–175° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45–1.60 (m, 2 H), 1.90–2.15 (m, 2 H), 2.10–2.95 (m, 5 H), 3.03 (brd, J=10.5 Hz, 1 H), 3.26 (dd, J=14.1, 3.8 Hz, 1 H), 3.68 (brd, J=12.4 Hz, 2 H), 3.95–4.05 (m, 3 H), 4.51 (dd, J=10.0, 4.0 Hz, 1 H), 6.58 (d, J=7.8 Hz, 1 H), 6.63 (d, J=8.1 Hz, 1 H), 6.75–6.95 (m, 3 H), 7.05 (d, J=8.7 Hz, 2 H), 11.60 (s, 1 H), 11.85 (brs, 1 H); MS (ES) m/z: 512.0 (MH+); HRMS Calcd. for C25H30N5O5S (MH+): 512.1968. Found: 512.1982.
Reaction SMILES: N1C=CC=CC=1.C(B1OB(C=C)OB([CH:17]=[CH2:18])O1)=C.[OH:19][C:20]1[C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O.CO.ClCCl>[N+:30]([C:21]1[C:20]([O:19][CH:17]=[CH2:18])=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:32])=[O:31]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=COc1cccc(C(=O)OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 50.4 %

Procedure:
A mixture of copper (II) acetate (11.98 g, 65.9 mmol) and dichloromethane (80 mL) was stirred at room temperature for 10 minutes, before the addition of 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane compound with pyridine (1:1) (10.63 g, 44.2 mmol, 0.67 eq), methyl 3-hydroxy-2-nitrobenzoate (U.S. Publication No. 2012/0035194 A1 [0202]) (13 g, 65.9 mmol), pyridine (26.7 mL, 330 mmol), and molecular sieves (1 g). The resulting deep blue mixture was stirred at room temperature for 5 days, with the reaction mixture opened to the air. The reaction mixture was filtered through a pad of CELITE®, washing with dichloromethane. The filtrate was washed with 3M aqueous ammonium acetate (2×), water, and brine, and then dried and concentrated in vacuo. The crude product mixture was purified via silica gel chromatography (hexanes/EtOAc) to give Intermediate A1A (7.42 g, 33.2 mmol, 50.4% yield). HPLC: RT=2.487 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=246 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.77 (dd, J=7.8, 1.2 Hz, 1H), 7.55 (t, J=8.1 Hz, 1H), 7.38 (dd, J=8.4, 1.3 Hz, 1H), 6.61 (dd, J=13.6, 5.9 Hz, 1H), 4.95 (dd, J=13.6, 2.4 Hz, 1H), 4.69 (dd, J=5.9, 2.4 Hz, 1H), 3.93 (s, 3H), 1.56 (s, 1H), 0.03 (s, 1H).
Reaction SMILES: [Li].C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[C:22]12[CH2:33][O:32][CH2:31][C:30]1=[CH:29][C:28]1[CH2:27][O:26][CH2:25][C:24]=1[CH:23]=2.O>O1CCCC1>[CH3:33][C:22]1[C:30]([CH2:31][OH:32])=[CH:29][C:28]2[CH2:27][O:26][CH2:25][C:24]=2[CH:23]=1
Reactant: c1c2c(cc3c1COC3)COC2
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1CO)COC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
To a mixture of lithium powder (15 g, 2.1 mol), 4,4′-di-tert-butylbiphenyl (5.0 g, 0.021 mol) and tetrahydrofuran (200 mL) was added a mixture of 5,11-dioxatricyclo[7.3.0.0^{3,7}]dodeca-1,3(7),8-triene (35 g, 0.21 mol) described in Production Example 1-4 and tetrahydrofuran (100 mL) at −78° C., followed by stirring at that temperature for 4 hours. Water (10 mol) was added at that temperature to the reaction mixture, and thoroughly stirred. The reaction mixture was allowed to warm to room temperature, and extracted with ethyl acetate after addition of a 2 N aqueous solution of hydrochloric acid (500 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound (10 g, 30% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[CH2:5][N:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]([F:18])([F:17])[F:16])=[N:7]1.C([O-])(=O)C.[NH4+].CC(C)=O>[Cl-].[Cl-].[Cl-].[Ti+3].O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH2:22])[CH2:5][N:6]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][C:8]([C:15]([F:18])([F:17])[F:16])=[N:7]1
Reactant: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
To a mixture of 1-(3-methyl-4-nitrobenzyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (1.4 g), ammonium acetate (30.5 g), acetone (60 ml) and water (30 ml), 20% aqueous solution of titanium trichloride (27.5 g) was added at room temperature and the mixture was stirred at room temperature for 12 hours. After finishing the reaction, the mixture was extracted with ethyl acetate, washed with saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-aminobenzyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (1.19 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:5](=[O:26])[N:4]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=2)[C:3]1=[O:40].CC1(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(=[O:68])N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:1][C:2]1([CH3:41])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][S:15]([CH2:16][CH2:17][CH2:18][C:19]([F:24])([F:25])[C:20]([F:23])([F:22])[F:21])=[O:68])[C:5](=[O:26])[N:4]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([C:36]([F:38])([F:39])[F:37])[CH:28]=2)[C:3]1=[O:40]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCOCCOCCSCCCC(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCOCCOCCS(=O)CCCC(F)(F)C(F)(F)F
Yield: 88 %

Procedure:
Compound 37 described below was synthesized according to a method similar to that described in Example 2 using compound 36 as starting reagent replacing 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-1-{9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl}imidazolidine-2,4-dione. The expected compound is obtained in the form of a pale yellow oil with a yield of 88%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH:17]=3)=[C:11]([F:29])[CH:10]=2)[CH2:4]1.O[C:31]1[CH:35]=[CH:34][O:33][N:32]=1>>[O:33]1[CH:34]=[CH:35][C:31]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]4[CH2:21][CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH:17]=4)=[C:11]([F:29])[CH:10]=3)[CH2:4]2)=[N:32]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Product: O=C1O[C@@H](COc2ccon2)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1

Procedure:
PCT Application No. GB99/01753 (Publication No. WO 99/64417) describes the preparation of 5(R)-Hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one (Reference Example 4 of GB99/01753), which is reacted under Mitsunobu conditions with 3-hydroxyisoxazole to give 5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one (Reference Example 5 of GB99/01753). Purification (by column chromatography) and subsequent reaction with 1-chloroethyl chloroformate and work-up gives 5(R)-Isoxazol-3-yloxymethyl-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one (Reference Example 6 of GB99/01753).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[CH2:31][N:32](CC)CC.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.CN>CN(C=O)C.[Cl-].[NH4+]>[CH3:31][NH:32][C:24]([C:23]1[CH:22]=[C:21]([CH:29]=[CH:28][CH:27]=1)[CH2:20][NH:19][C:17]([C:12]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:18])=[O:25]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-benzoic acid (70 mg, 0.2 mmol) in DMF (5 mL) was added Et3N (0.07 mL, 0.6 mmol) and PyBOP (100 mg, 0.2 mmol). After 15 minutes of stirring at room temperature, methylamine hydrochloride (15 mg, 0.22 mmol) was added. After 16 hours, the mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (20 mL), brine (20 mL) and dried over sodium sulfate. The crude product was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes. The material from the column was then crystallized from EtOAc/ether/hexanes to afford the title compound as a white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=3[CH3:30])=[CH:19][S:20][CH:21]=2)=[CH:13][CH:12]=1.CN(C)[CH:33]=[O:34]>O1CCCC1>[CH:33]([C:19]1[S:20][CH:21]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)[C:18]=1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[CH3:30])=[O:34]
Reactant: COc1ccc(-c2cscc2-c2ccc(C#N)cc2C)cc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2csc(C=O)c2-c2ccc(C#N)cc2C)cc1
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
A solution of freshly prepared LDA (0.8 mL, 1.64 mmol) in anhydrous tetrahydrofuran (7 mL) was added slowly a solution of 4-(4-(4-methoxyphenyl)thiophen-3-yl)-3-methylbenzonitrile (Scheme I, 3, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (500 mg, 1.637 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen at −78° C. After being stirred for 15 min., a solution of dimethylformamide (0.14 mL, 1.804 mmol) in anhydrous tetrahydrofuran (3 mL) was dropwise added. The resulting mixture was stirred for 1 h at −78° C., and at room temperature for 3 h. The reaction was quenched with water (50 mL), and extracted with ethyl acetate (40 mL×3). The combined organic extracts were washed with water (30 mL), brine (50 mL), dried over anhydrous sodium sulfate, evaporated, and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to afford 4-(2-formyl-4-(4-methoxyphenyl)thiophen-3-yl)-3-methylbenzonitrile (Scheme I, 4A, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (0.16 g, yield 29.3%) as a white solid (confirmed by NOE). 1H NMR (DMSO-d6 400 MHz): δ 9.46 (s, 1H), 8.31 (d, J=1.2 Hz, 1H), 7.83 (s, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 3.77 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:11](OCC)=O)=[C:5]([CH3:10])[C:6]=1[CH:7]([CH3:9])[CH3:8].C=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:11])=[C:5]([CH3:10])[C:6]=1[CH:7]([CH3:8])[CH3:9]
Reactant: CCOC(=O)c1[nH]c(C)c(C(C)C)c1C
Agent: C=O
Product: Cc1[nH]c(C)c(C(C)C)c1C

Procedure:
2,4-Dimethyl-3-isopropyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2,4,5-trimethyl-3-isopropyl-pyrrole. ##STR97##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[C:13]([NH2:17])=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1.[NH2:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[C:13]([NH:17][C:23]3[N:22]=[N:21][C:20]([NH2:19])=[CH:25][CH:24]=3)=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1
Reactant: Nc1ccc(Cl)nn1
Reactant: Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1ccc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nn1
Temperature: 150 °C
Yield: 12.7 %

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-ylamine (100 mg, 0.36 mmol), 3-amino-6-chloropyridazine (57 mg, 0.44 mmol), Pd2(dba)3 (8 mg, 0.009 mmol), Xantphos (21 mg, 0.036 mmol) and cesium carbonate (234 mg, 0.72 mmol) in dioxane (2.5 mL) was degassed with argon then heated at 150° C. for 30 minutes in a microwave reactor. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4-7% methanol in DCM) to afford the title compound as a beige solid (17 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.45 (d, J=0.9 Hz, 1H), 7.95-7.89 (m, 2H), 7.86-7.84 (m, 2H), 7.76 (dd, J=9.1, 7.2 Hz, 1H), 7.62 (d, J=9.7 Hz, 1H), 7.57-7.53 (m, 1H). LCMS (Method B): RT=2.56 min, m/z: 372 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[N:3]=1.[NH4+:21].[OH-]>[Cl-].[Na+].O>[NH2:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Oc2ccc(CN3CCCC3)cc2)n1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc(Oc2ccc(CN3CCCC3)cc2)n1
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine (20 g) and Cu powder (1 g) in concentrated NH4OH (250 mL, aq) and IpOH (60 mL) was heated at 100° C. in a sealed flask for 48 h. After cooling to RT, brine (300 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residues were filtered through silica gel pad eluting with MeOH/CH2Cl2 (5%). The filtrate was concentrated to dryness, then 50 mL of MeOH was added. After stirring for a while the solid was filtered to give the title compound. MS m/z: 270 (M+1). Calc'd for C16H19N3O-269.3
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OC1CCNCC1
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Reaction time: 1 h
Yield: 76.7 %

Procedure:
2-chloro-5-nitrobenzonitrile (36 g) and 4-hydroxypiperidine (50 g) were added to ethanol (300 ml), and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-(4-hydroxypiperidin-1-yl)benzonitrile (37.4 g), melting point: 114–115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([OH:8])=[N:6][CH:7]=1.[Cl-].[Ca+2].[Cl-]>[Fe].C(O)C>[NH2:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1cc(Cl)cnc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To an 80% aqueous ethanol suspension (150 ml) of 5-chloro-3-nitropyridin-2-ol (15.0 g) and calcium chloride (9.54 g) was added iron powder (24.0 g), followed by stirring at room temperature for 30 minutes, and further under heating at reflux for 1 hour. After the temperature was brought back to room temperature, the reaction suspension was filtered through Celite. Water was added to the filtrate, and extracted 8 times with a methanol-dichloromethane (1:10) mixed solvent. The collected organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 3-amino-5-chloropyridin-2-ol (8.86 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:10][CH2:11][CH:12]1[O:14][CH2:13]1.O.[OH-].[Li+]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:13][CH:12]([OH:14])[CH2:11][CH3:10])#[N:2]
Reactant: CCC1CO1
Reactant: N#Cc1cccc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCC(O)COc1cccc(C#N)c1

Procedure:
is obtained analogously to Example H1 by using 20.7 g of 3-cyanophenol, 13.8 g of α-butylene oxide and 0.5 g of lithium hydroxide monohydrate in a yield of 25.9 g in the form of an oil; b.p. 116°-118° C./0.04 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[CH:25]=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[C-]#N.[Na+].C[C:35](O)=[O:36]>CO.C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]([O:36][CH3:35])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(=O)O
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a solution of the aldehyde of Step 6 (17.26 g, 41.7 mmol) in 1.5 L of MeOH:THF 2:1, NaCN (20 g, 408 mmol), AcOH (5.7 mL, 98.9 mmol) and activated MnO2 (90 g, 1.01 mol) were added and the mixture was stirred for 16 h. The inorganic solid was then removed by filtration and washed with EtOAc. To the combined organic phases, 25% aq NH4OAc (1.7 L) was added. The two phases were separated and the aqueous layer was reextracted with EtOAc. The organic phases were washed with brine and dried over Na2SO4. Flash chromatography of the residue on silica with toluene and EtOAc:toluene 2.5:97.5 afforded 15.63 g (84%) of the title ester.