Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=1F>>[Cl:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][C:18]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)[NH2:23]
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC

Procedure:
N1 was prepared from 6,7-dimethoxyquinolin-4-ol and 2-chloro-1-fluoro-4-nitrobenzene following the general procedure reported in Preparative Example 1 Step 1-2. 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.92 (s, 6H), 5.45 (br s, 2H), 6.28 (d, J=5.3 Hz, 1H), 6.61 (dd, J=8.7 Hz, J=2.6 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 7.36 (s, 1H), 7.50 (s, 1H), 8.42 (d, J=5.3 Hz, 1H). MS (ES) C17H16ClN2O3 requires: 330. Found: 331 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].C1C=CC=CC=1>C(O)C>[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:11]=2[C:10](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:9]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2Cl)Cc2nncc(C(F)(F)F)c21
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2nncc(C(F)(F)F)c21

Procedure:
To a solution of 7-(2-chlorophenyl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.335 g) and aminoguanidine hydrochloride (165 mg) in ethanol (10 ml) were added methanesulfonic acid (0.3 ml) and benzene (10 ml), and the mixture was refluxed for 80 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in acetone, and to the solution was added methanesulfonic acid (0.15 ml). Precipitated crystals were filtered, washed with acetone and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-trifluoromethyl-5,6,7,8-tetrahydrocinnoline methanesulfonate (Compound 136) (0.240 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[O:5]
Reactant: COC(=O)c1cccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ncccc1C=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
A solution of methyl 2-methylnicotinate (0.5 g, 3.3 mmol) in THF (16 mL) at 0° C. was treated dropwise with lithium aluminum hydride in THF (6.6 mL, 1 M), stirred at 0° C. for 1.5 hours, treated with ethyl acetate (3 mL), warmed to 25° C., and partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. A solution of the residue (0.391 g) in dichloromethane (16 mL) was treated with MnO2 (2 g), stirred at 25° C. for 68 hours, filtered through celite®, and the solvent was evaporated to give the title compound (0.303 g, 75% yield), which was used without further purification.
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:32][C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]1COCC1.[Li]C.[NH4+].[Cl-]>C(#N)C.O>[CH2:1]([C@@:8]12[CH2:21][C@:20]([OH:22])([CH3:40])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:32][C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)[C@](C)(O)C[C@@]21Cc1ccccc1
Temperature: -17 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a flame dried 50 mL round bottom flask was added the (4bR,7R,8aR)-4b-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-6-oxo-7-phenyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide (0.28 g, 0.54 mmol) in a THF (5 mL). The solution was cooled to −17° C. in an ice/acetone bath. To the reaction was added MeLi*LiBr (0.1 mL). After 1 hour the LCMS indicated that starting material remained so an additional 0.15 mL was added. The reaction stirred to room temperature over 2 hours. By HPLC, 2.5% of the starting material remained. To the reaction was added NH4Cl slowly and off gassing was observed. The reaction was diluted to 125 mL with acetonitrile and water. The reaction was purified by reverse phase chromatography then was lyophilized. The resulting dried powder was dissolved in acetonitrile and water again with two drops of concentrated HCl. The solution was lyophilized to dryness. This afforded the title product (231.4 mg) as the HCl salt in 73% yield. LRMS ES+ 533.1 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.23-1.28 (m, 3H) 1.53-1.62 (m, 1H) 1.90-2.20 (m, 3H) 2.70-2.74 (m, 3H) J=8.26 Hz, 2H) 6.84-6.92 (m, 2H) 6.99-7.10 (m, 3H) 7.13-7.29 (m, 3H) 7.45 (dd, J=8.15, 1.91 Hz, 1 H) 7.56-7.65 (m, 2H) 7.77 (d, J=1.81 Hz, 1H) 7.88 (dd, J=8.26, 5.84 Hz, 1H) 8.51-8.63 (m, 2H).
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:18][CH2:19][C:20]#[N:21]>>[C:19]([CH2:20][NH:21][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:17][CH:16]=1)#[N:18]
Reactant: N#CCN
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1ccc(C(=O)NCC#N)cc1

Procedure:
General procedure F was used to couple 0.1 g (0.42 mmols) of 2 and 0.065 g of amino acetonitrile. The title product was purified with flash chromatography using a solvent system of ethyl acetate and hexanes (2:3) to yield 0.104 g (0.38 mmols). 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=8.3, 2H), 7.25 (d, J=7.6, 2H), 6.78 (t, J=5.5, 1H), 4.37 (d, J=5.8, 2H), 2.81-2.51 (m, 2H), 1.62 (dt, J=7.4, 22.1, 3H), 1.26 (s, 10H), 0.87 (t, J=6.7, 3H). 13C NMR (75 MHz, CDCl3) δ 167.32, 148.82, 130.03, 129.08, 127.46, 117.30, 77.67, 77.25, 76.83, 36.09, 32.06, 31.35, 29.62, 29.44, 28.19, 22.86, 14.31.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21]>CO.C(O)C.[Pd]>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:25][CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)CCN
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)CCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (277 mg) in methanol (10 mL) was added 2-methanesulfonyl-ethylamine (234 mg) and the reaction stirred at room temperature for 16 h. The solvent was reduced in vacuo and the residue redissolved in ethanol (50 mL). Palladium on carbon (20 mg) was added and the reaction stirred at room temperature under a hydrogen balloon for 48 h. The reaction was then filtered through Celite and the filtrate reduced in vacuo to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methanesulfonyl-ethyl)-amine as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)=[CH:39][CH:40]=2
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-trifluoromethylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 557 (M+H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC2(CC(N=[N+]=[N-])C2)C1

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.3.). Starting with 1.62 g (5.30 mmol) of tert-butyl 2-methanesulfonyloxy-6-azaspiro[3.4]octane-6-carboxylate (isomer 1′), described in Example 12 (step 12.1.), and 0.68 g (10.61 mmol) of sodium azide, the product is obtained in the form of a yellow oil, which is used without further purification in the following step.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1.[C:19](B1OC(C)(C)C(C)(C)O1)([CH3:21])=[CH2:20].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:21][C:19]([C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1)=[CH2:20]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1csc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (334 mg) obtained in Example 1, steps 1-3, isopropenylboronic acid pinacol ester (168 mg), saturated aqueous sodium carbonate solution (6 ml), tetrakis(triphenylphosphine)palladium (32.5 mg) and DME (9 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere, and poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→30% ethyl acetate/hexane) to give the title compound (270 mg, 91.5%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1n[nH]c2ncccc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
3-Methyl-pyrazolo[3,4-b]pyridine (1 mmol, 1 eq.) was suspended into a mixture of 1:1 fuming nitric acid and concentrated sulfuric acid (1 mL:1 mL), and the resultant mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled to rt, and poured into a mixture of sodium bicarbonate and ice. The resultant solution was warmed up to rt and extracted with 300 mL of EtOAc. The organic extract was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to provide 70.2 mg of 3-methyl-5-nitro-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[S:24].Cl>ClCCl.O>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:23](=[S:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=3)=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: Cc1cccc(C(=S)Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=S)c3cccc(C)c3)c(O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.26 g of aluminium trichloride are suspended in 70 ml of dichloromethane and, over a period of 15 minutes, 10.19 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester are added dropwise at from 20° to 30°. Stirring is carried out for 30 minutes, 20.8 g of m-methylthiobenzoyl chloride are added dropwise over a period of 20 minutes and the whole is stirred for 4 hours at room temperature, poured into a mixture of 200 g of ice, 20 ml of concentrated hydrochloric acid and 200 ml of water, stirred for 30 minutes and extracted by shaking twice with 50 ml of dichloromethane each time and once with 50 ml of a mixture of trichloromethane and methanol (3:1). The organic phases are combined, washed twice with water, dried over magnesium sulphate, treated with kieselguhr and concentrated by evaporation. Chromatography over silica gel using hexane/ethyl acetate (4:1) as eluant yields 4-(m-methylthiobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester in the form of a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:16](N(CC)C(C)C)(C)[CH3:17].C(I)C>CN(C=O)C>[CH2:16]([N:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][C:7]1[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Cc2ncc[nH]2)cc1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCn1ccnc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Yield: 20.5 %

Procedure:
To a solution of 2-(4-nitro-benzyl)-1H-imidazole (1.58 g, 7.37 mmol) in DMF (10 mL) was added N,N-diisopropylethyl amine (1.93 mL, 11.05 mmol) and heated to 5° C. for 30 min. Ethyl iodide (1.18 mL, 7.37 mmol) was added dropwise and the reaction mixture heated to reflux for 6 h. The solvent was evaporated under reduced pressure, the residue dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, evaporated and the residue purified by column chromatography over silica gel (60-120 mesh) using 3% methanol/chloroform as eluent to afford 1-ethyl-2-(4-nitrobenzyl)-1H-imidazole (0.35 g, 21%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([NH:35][C:36]4[CH:37]=[C:38]([C:42]([O:44]C)=[O:43])[N:39]([CH3:41])[CH:40]=4)=[O:34])[N:30]([CH3:32])[CH:31]=3)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([NH:35][C:36]4[CH:37]=[C:38]([C:42]([OH:44])=[O:43])[N:39]([CH3:41])[CH:40]=4)=[O:34])[N:30]([CH3:32])[CH:31]=3)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cc1C(=O)O
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Methyl 4-(4-(4-(4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate (510 mg, 0.82 mmol) in 10 ml of DMA was added 0.8 g of LiOH in 10 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 to form precipitates. The precipitates were filtered, washed with water and dried over P2O5 under vacuum to afford 363 mg (73%) of the title product. 1H NMR (DMF-d7) 10.31 (s, 1H), 10.18 (s, 1H), 10.11 (s, 1H), 9.10 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 4.10 (s, 1H), 3.98 (s, 1H), 3.95 (s, 1H), 3.93 (s, 1H), 1.47 (s, 9H); 13C NMR 162.16, 160.05, 159.90, 157.20, 154.31, 137.88, 135.35, 124.56, 124.39, 123.51, 123.09, 121.76, 120.09, 119.83, 118.96, 115.32, 109.53, 105.58, 102.27, 79.32, 38.13, 36.02, 35.81, 34.88, 28.79; MS m/z−606.2 (M−H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].C[O:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1.[OH-].[Na+].Cl>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]2[C:17]([OH:16])=[N:18][S:19](=[O:24])[N:20]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)N=C1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)N=C2O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (4.15 g; 17.9 mmoles) in 50 ml of methanol was added dropwise over a 30 minute period to a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.91 g; 17.9 mmoles) in 350 ml of methanol that had been cooled in an ice-water bath. The reaction mixture was treated with a solution of sodium hydroxide pellets (3.58 g; 89.5 mmoles) in methanol. After stirring overnight at ambient temperature, the mixture was neutralized with 14.9 ml (89.5 mmoles) of aqueous 6.0 N HCl and after 10 minutes was evaporated under reduced pressure. The solid residue was triturated for 2 hours with 70 ml of water at ambient temperature and filtered to give product. Recrystallization from water yielded the title compound, mp 148°-151°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[N:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1
Reactant: Clc1ccccn1
Reactant: OC1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: OC1CCN(c2ccccn2)CC1
Yield: 27.3 %

Procedure:
A solution of piperidin-4-ol (100 mg, 0.99 mmol), desired 2-chloropyridine (0.99 mmol, 1.0 equiv.), and DIPEA (345 μL, 1.98 mmol) in isopropanol (1.5 mL) was heated by microwave irradiation at 160° C. for 2.5 h. The reaction was purified directly by silica gel chromatography to give the desired 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (using 5-bromo-2-chloropyridine, 5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol was isolated in 27% yield, 69.1 mg, 0.27 mmol; using 5-trifluoromethyl-2-chloropyridine, 5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol was isolated in 62% yield, 150.1 mg, 0.61 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:16]([C:24](O)=[O:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Reactant: O=C(O)C(=O)c1ccccc1
Solvent: CCOCC
Product: O=c1c(-c2ccccc2)nc2ccccc2n1-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of N-(4-chlorophenyl)benzene-1,2-diamine (12.0 g) in a minimum quantity of ether was added benzoylformic acid (7.5 g) dissolved in ether and the mixture was stirred for 8 hours. The resulting precipitate was filtered, dried, and recrystallised from ethanol giving the title compound (11.0 g) mp 214.5°-216.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15](Cl)[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH-:30].[Na+].O>CO>[CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15]([SH:30])[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(Cl)cc12
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(S)cc12
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A solution of 2-(1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.24 mmol) prepared in Example 658 and sodium hydrosulfide (26.7 mg, 0.48 mmol) in methanol (2 ml) was refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. Water was added to the resulting solid. The reaction mixture was stirred for 30 minutes and then filtered. The resulting solid was washed with water 3 times and then dried to give 68 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)c(I)cc1OCc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OC)c(OCc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-benzyloxy-2-iodo-5-methoxybenzoic acid (reference example 5-1) (2 g), 2-iodoethane (0.5 mL), potassium carbonate (1.08 g) and N,N-dimethylformamide (17 mL) was stirred at room temperature for 2 hours. Water was added to the mixture. Insoluble materials were collected by filtration to give the title compound (2.07 g).