Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O:29]CC)=[O:28].[OH-].[K+]>CCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of ethyl(1RS,2RS,3RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (90 mg, 0.22 mmol) in EtOH (2 ml) containing a few drops of THF was added 6M KOH (0.22 ml, 1.32 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted with EtOAc. The EtOAc extract was washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford the title compound (40 mg, 49%).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH2:12](O)[CH3:13]>OS(O)(=O)=O>[NH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:12][CH3:13])=[O:8])=[CH:10][CH:11]=1)[NH2:2]
Reactant: CCO
Reactant: NNc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(NN)cc1

Procedure:
5.0 g of 4-hydrazinobenzoic acid are dissolved in 70 ml of ethanol and 3 ml of concentrated H2SO4. The mixture is heated at reflux for five hours, the ethanol is evaporated, the residue is then taken up in a saturated K2CO3 solution and then extraction is carried out with AcOEt. 5.9 g of the expected compound are obtained in the form of a powder.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(C(F)(F)F)cc1
Reactant: CSc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Yield: 88 %

Procedure:
A solution of 4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.12 mmol) in dioxane/H2O (3:1, 4.8 mL) was mixed with 2-methylthiophenyl boronic acid (30.4 mg, 0.18 mmol) and K2CO3 (50.1 mg, 0.36 mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (2.8 mg, 0.0024 mmol). The reaction tube was sealed and heated with “Smith Creator” (microwave, 150° C.) for 15 minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (88%): MS (ES) m/z 503 (M+H)+; 1H-NMR(CDCl3) δ 2.48 (s, 3H), 2.65 (s, br, 2H), 3.70 (m, br, 5H), 6.20 (m, br, 1H), 6.45 (m, 1H), 7.43 (m, 6H), 7.68 (m, 1H), 7.83 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[N:16]([CH3:26])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].NC1C=C2C(=CC=1)NC=C2CC1C=CC(C(OC)=O)=CC=1OC>O1CCCC1.[Pd]>[NH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:26])[CH:15]=[C:14]2[CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [Pd]
Agent: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Yield: 97.5 %

Procedure:
A solution of (E) (0.56 g.) in tetrahydrofuran (30 ml.) was hydrogenated in the presence of palladium-on-carbon (10% w/w; 0.1 g.), as described for the amino ester (A) in Example 1, to give methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.50 g., 98%) as pale yellow foam; NMR: 3.6 (s, 3 H, NCH3), 3.8 (s,3 H, CO.OCH3), 3.9 (br s,5 H, OCH3 and CH2.Ar), 4.45 (br,2 H, NH2), 6.54 (m,2 H), 6.86 (s,1 H), 7.04 (m,2 H), 7.40 (m,2 H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N+:35]([O-:37])=[O:36])=[C:30](B(O)O)[CH:31]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N+:35]([O-:37])=[O:36])=[C:28]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:27]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: O=[N+]([O-])c1ccc(Cl)cc1B(O)O
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(Cl)ccc1[N+](=O)[O-]
Yield: 7 %

Procedure:
5′-Chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid was prepared in 7% yield (for two steps) from 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6) and 5-chloro-2-nitrophenylboronic acid (available from Combi-Blocks Inc.) using General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode. 1H NMR (300 MHz, DMSO-d6) δ 13.29 (br s, 1H), 8.60 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.29-8.37 (m, 2H), 8.20 (d, J=8.9 Hz, 2H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 7.73-7.82 (m, 2H), 7.60 (d, J=2.3 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)[CH3:2].[Cl-].[CH3:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[CH:13]=[N+:14]([CH3:16])[CH3:15]>>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:13]([N:14]([CH3:15])[CH3:16])[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[O:10][CH3:9])[CH3:2]
Reactant: COc1ccccc1C=[N+](C)C
Reactant: CCn1cccc1
Agent: [Cl-]
Product: CCn1cccc1C(c1ccccc1OC)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-1H-pyrrole and (2-methoxy-benzylidene)-dimethyl-ammonium chloride.
Reaction SMILES: [C:1]([C:3](=[N:7][O:8][CH2:9][CH3:10])[C:4](N)=[O:5])#[N:2].C(=O)(O)[O-:12].[Na+].Cl.[NH2:17][OH:18]>O>[C:4]([C:3](=[N:7][O:8][CH2:9][CH3:10])[C:1](=[N:17][OH:18])[NH2:2])([OH:12])=[O:5]
Reactant: O=C([O-])O
Reactant: CCON=C(C#N)C(N)=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCON=C(C(=O)O)C(N)=NO
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a suspension of 2-cyano-2-ethoxyimino-acetamide (112.8 g, 0.8 mol) and sodium bicarbonate (134.4 g, 1.6 mol) in water (258 mol), hydroxylamine hydrochloride (61.6 g, 0.88 mol) in water (86 ml) was added dropwise at 80° to 85° C. The mixture was stirred at the same temperature for 3 hrs., and then treated in the same procedure as described in Preparation example 5 to give 2-carboxy-2-ethoxyimino-acetamidoxime (122.5 g) as crystals containing 28.6% of brine. Practical yield: 122.5×0.286=87.5 g. Yield: 62.5%.
Reaction SMILES: C(O[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1C(F)(F)F)CCCCCCC.CCOC(C)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C(Cl)Cl.CO>[N:29]([CH2:17][C:16]([C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)=[O:18])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCOc1ccc(C(C)=O)cc1C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (D1) (0.5 g, 1.0 equivalent) in CH2Cl2/MeOH (4:1, 10 mL) was added Bu4NBr3 (0.76 g, 1.0 equiv). The reaction mixture was stirred at room temperature for 3 hours. TLC (4:1, Hex/EtOAc), Rf=0.6. The solvent was removed in vacuo, and re-dissolved in DMF (10 mL). NaN3 (0.31 g, 3.0 equiv) was added to the reaction and the resulting mixture was then stirred at room temperature for 2 hrs. The solvent was removed in vacuo and the product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) to give the azido-acetophenone product. TLC (4:1, Hex/EtOAc), Rf=0.4. The residue was then dissolved in concentrated HCl (1.0 mL) and MeOH (20 mL). 10% Pd/C (100 mg) was added and the mixture stirred under an atmosphere of H2 (g) for 3 hours. The reaction mixture was then filtered and evaporated to dryness to give the title product as a yellow solid 98% (570 mg yield). TLC (4:1, Hex/EtOAc), Rf=0.6.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:20]=[C:19]([F:21])[C:17]([NH2:18])=[C:16]([Cl:22])[CH:15]=1.CCN(C(C)C)C(C)C.[CH:32]1([C:35]([N:37]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43]([NH:45][NH2:46])=[O:44])[CH2:38]2)=[O:36])[CH2:34][CH2:33]1>ClCCl>[Br:13][C:14]1[CH:20]=[C:19]([F:21])[C:17]([NH:18][C:2]([NH:46][NH:45][C:43](=[O:44])[CH2:42][C@@H:39]2[CH2:40][CH2:41][N:37]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH2:38]2)=[O:4])=[C:16]([Cl:22])[CH:15]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(Br)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1c(F)cc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 5 h

Procedure:
To a round bottom flask was added triphosgene (2.63 mmol) and dichloromethane (20 mL) under nitrogen, and the solution was cooled to −78° C. In a separate vial, 4-bromo-2-chloro-6-fluoroaniline (6.46 mmol) was dissolved in dichloromethane (20 mL) and Hunig's base (17.2 mmol) was added. This solution was slowly added to the cooled solution and then the reaction was allowed to warm to room temperature. After 5 h, analysis by LCMS indicated desired intermediate formation. The reaction was cooled again to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (4.31 mmol) in dichloromethane (5 mL) was added slowly. The reaction was allowed to warm to room temperature and stirred for 70 h. Analysis by LCMS indicated desired product formation. The mixture was concentrated and suspended in water (130 mL). Potassium carbonate (9.85 mmol) was added and the mixture was heated at reflux (110° C.) for 18 h. Analysis by LCMS indicated a small amount of desired product (and other major by-products). The reaction was cooled to room temperature and the pH was adjusted to ˜6 with 1N and 6N aq HCl, and then poured into a separatory funnel containing ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to an oil. The residue was purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4, and concentrated to afford the title product as an off-white solid (12 mg, 1% over two steps). MS(ES)+ m/e 443.0, 445.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][CH2:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([CH:44]=O)[CH2:40][CH2:39]2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:44][C@H:41]1[CH2:42][CH2:43][C@H:38]([CH2:37][CH2:36][C@H:33]2[CH2:32][CH2:31][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)[CH2:39][CH2:40]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=O)CC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=C(Br)Br)CC2)CC1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.4 g of tetrabromomethane in 80 ml of methylene chloride was placed at -15° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 7.0 g of triphenylphosphine in 20 ml of methylene chloride. The clear deep orange solution was stirred at -5° C. for a further 10 minutes and then a solution of 1.95 g of the trans-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise within 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes, then poured into 600 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate was digested with 300 ml of hexane, left to stand at 0° C. for 30 minutes, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.0 g) on silica gel with hexane gave 2.68 g (89.2%) of trans-1-(2,2-dibromovinyl)-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane which contained about 10% of the corresponding epimeric cis compound in accordance with NMR spectroscopic analysis and which was used without additional purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)(=O)C>[C:30]1([NH:29][C:2]2([C:26]#[N:27])[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: Nc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccccc4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.57 mmol), sodium cyanide in 5 ml acetic acid was stirred at room temperature for 1 hour. To the reaction mixture aniline was added and was stirred at 60° C. for overnight. The solvent was removed in vacuum and the residue was extracted with chloroform and was washed with water and dried. Evaporation of solvent followed by silica gel chromatographic purification afforded the title compound in 51% yield. M.P. 81-85° C. and MS (M+1)=452 (MH+, 100%) for M.F.=C24H26FN5O3.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1>CCOCC.C1COCC1>[CH2:14]1[O:15][C:16]2([CH2:21][CH2:20][C:19]([OH:22])([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:18][CH2:17]2)[O:23][CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2cccnc2)CCC2(CC1)OCCO2
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-BuLi (2.5 M in hexanes, 88.4 mL, 221.0 mmol) in Et2O (250 mL) at −78° C. was added a chilled solution (−78° C.) of 3-bromopyridine (35 g, 221.0 mmol) in Et2O (125 mL) via cannula. After being stirred for 10 min, a solution of 1,4-cyclohexanedione monoethylene ketal (34.5 g, 221.0 mmol) in THF (125 mL) was added via cannula The reaction mixture was stirred for 1 h at −78° C., then slowly warmed to −20° C. over 1 h. The reaction was quenched by pouring into saturated aqueous NH4Cl, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL×3) and the combined organic layers were washed with brine (200 mL), dried with MgSO4 and concentrated in vacuo. The crude product was triturated with Et2O to afford 4-hydroxy-4-(3-pyridyl)cyclohexanone ethylene ketal as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>N1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][NH2:23])[C:7]=2[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2ccnc(Cl)c2-c2ccncc2)cc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1nccc(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a stirring solution of 2-chloro-4-(4-chlorophenyl)-3,4′-bipyridine (1.3 g, 4.3 mmol) in pyridine (5 mL) at room temperature under argon was added hydrazine monohydrate (2.5 mL, 51.5 mmol). The reaction mixture was stirred at reflux under argon for 15 h. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. Water (25 mL) was added to the residue while stirring and a precipitate formed. The precipitate was collected by filtration and washed with water (15 mL×2). After drying under reduced pressure at elevated temperature, 1.0 g of the title compound was obtained as a yellow solid. HPLC/MS: retention time=1.68 min, [M+H]+=297.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1nc(-c2ccc(F)cc2)cs1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a stirred solution of ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoate (0.900 g, 3.07 mmol) in 1:1:1 THF/ethanol/water (15 mL) was added lithium hydroxide monohydrate (0.451 g, 10.7 mmol). After overnight stirring, the reaction was concentrated and redissolved in water (80 mL). The solution was washed with ether (1×50 mL), acidified with the addition of 1 N HCl (15 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried (Na2SO4) and concentrated to afford 2-(4(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid as a pale golden solid (0.808 g, 99%).
Reaction SMILES: CC(C)CNC1C=C(NC(OCC)=[O:14])C=CC=1N.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=O.[CH3:26][CH:27]([CH3:48])[CH2:28][N:29]1[C:33]2[CH:34]=[C:35]([NH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[C:44]([F:47])([F:46])[F:45]>C1(C)C=CC=CC=1>[F:45][C:44]([F:47])([F:46])[C:30]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][C:33]=1[N:29]([C:21]([C:20]([F:25])([F:24])[F:19])=[O:23])[CH2:28][CH:27]([CH3:48])[CH3:26])=[O:14]
Reactant: CCOC(=O)Nc1ccc2nc(C(F)(F)F)n(CC(C)C)c2c1
Reactant: CCOC(=O)Nc1ccc(N)c(NCC(C)C)c1
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1ccc(NC(=O)C(F)(F)F)c(N(CC(C)C)C(=O)C(F)(F)F)c1

Procedure:
In yet another example, when 2-(2-methylpropylamino)-4-(ethoxycarbonylamino)aniline (R is 2-methylpropyl, X is hydrogen) (13) was treated with trifluoroacetic acid in toluene as described above (Step D of Example 7), a 1:1 mixture of the intermediate 1-(2-methylpropyl)-2-trifluoromethyl-6-ethoxycarbonylaminobenzimidazole (6), and the uncyclized intermediate, N-trifluoromethylcarbonyl-2-[(trifluoromethylcarbonyl)(2-methylpropyl)amino]-4-(ethoxycarbonylamino)aniline (14) was obtained. Treatment of the mixture of the intermediate benzimidazole (6) and (14) with potassium carbonate and water in methanol resulted in the direct conversion of intermediate (14) to the intermediate benzimidazole (6).
Reaction SMILES: Cl[C:2]([CH3:16])([CH3:15])[CH:3]([N:13]=[O:14])[CH2:4][C:5]1[N:6]=[C:7]([N+:10]([O-:12])=[O:11])[NH:8][CH:9]=1.[NH2:17][CH2:18][CH2:19]CN.[C:22](#N)C>>[NH2:17][CH2:18][CH2:19][CH2:15][C:2]([CH3:16])([CH3:22])[C:3](=[N:13][OH:14])[CH2:4][C:5]1[N:6]=[C:7]([N+:10]([O-:12])=[O:11])[NH:8][CH:9]=1
Reactant: NCCCN
Reactant: CC#N
Reactant: CC(C)(Cl)C(Cc1c[nH]c([N+](=O)[O-])n1)N=O
Product: CC(C)(CCCN)C(Cc1c[nH]c([N+](=O)[O-])n1)=NO
Temperature: 50 °C

Procedure:
3-Chloro-3-methyl-1-(2-nitroimidazolyl)-2-nitrosobutane (1.00 g, 4.06 mmol, Example 1) was added in portions over a period of 20 minutes to a stirred solution of 1,3-diaminopropane (1.0 g, 13.50 mmol) in dry acetonitrile at 50° C. After the addition, the reaction mixture was maintained at 50° C. for an additional 30 minutes. The reaction mixture was then cooled and filtered to provide the title compound as a yellow colored solid. For further purification, the solid was suspended in a small amount of water, stirred and filtered to afford the title product in >97% purity; yield: 0.78 g, (68%); mp. 136-137° C. 1H NMR (DMSO-d6) δ 1.19 [s, 6H, C(CH3)3], 1.37 (m, CH2CH2CH2), 1.52 (bs, 1N, NH), 2.21 & 1.54 (2t, 4H, NHCH2), 5.22 (s, 2H, imida-CH2), 7.05 & 7.27 (2s, 2H, imida-ring H) and 11.42 (bs, 1H, NOH). MS m/e 285 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[B:13](OC)([O:16][CH3:17])[O:14][CH3:15].CCOCC>CCCCCC.C1COCC1>[CH3:15][O:14][B:13]([O:16][CH3:17])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COB(OC)OC
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COB(OC)c1cccnc1
Temperature: 25 °C

Procedure:
n-Butyl lithium (31.3 ml of a 1.6M solution in hexane) was added to a stirred solution of 3-bromopyridine (4.8 ml) and trimethyl borate (6.2 ml) in dry THF (100 ml) at a rate such that the temperature did not exceed -65° C. The mixture was allowed to warm to ambient temperature over 16 hours and was filtered. The solid was washed with ether, combined with more solid obtained from the filtrate and rewashed with ether to give dimethoxy-(3-pyridyl)borane (3.5 g) as a solid, 1H NMR (CD3OD): 3.4 (s, 6H), 7.2 (m, 1H), 7.9 (m, 1H), 8.2 (dd, 1H), 8.6 (s, 1H); mass spectrum (+ve CI): 152 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1.C([O-])([O-])=[O:22].[K+].[K+].OO.O>CS(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:22])=[CH:15][N:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ncc(Oc2ccc(C#N)cn2)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncc(Oc2ccc(C(N)=O)cn2)c2ccccc12

Procedure:
To a solution of 6-(1-methylisoquinolin-4-yloxy)nicotinonitrile (Preparation 18) (200 mg, 0.77 mmol) in DMSO (5 mL) was added K2CO3 (53 mg, 0.38 mmol) and H2O2 (30% w/v, 120 μL, 1.1 mmol). After 1 h water (20 mL) was added and the mixture extracted with EtOAc (3×50 mL). The organic phase was washed with water (2×30 mL), NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (0.5 NH3: 5 MeOH: 95 DCM) to give the title compound: RT=2.11 min; m/z (ES+)=280.1 [M+H]+.