Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=2[N:11]=1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]2[N:29]=[CH:30][S:31][C:27]=2[CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[S:31]1[C:27]2[CH:26]=[C:25]([NH:24][C:19]([C:17]3[CH:16]=[CH:15][C:13]4[NH:14][C:10]([NH:9][C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[C:2]([F:22])([F:23])[F:1])=[N:11][C:12]=4[CH:18]=3)=[O:20])[CH:33]=[CH:32][C:28]=2[N:29]=[CH:30]1
Reactant: O=C(O)c1ccc2[nH]c(Nc3ccccc3C(F)(F)F)nc2c1
Reactant: Nc1ccc2ncsc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ccc2ncsc2c1)c1ccc2[nH]c(Nc3ccccc3C(F)(F)F)nc2c1

Procedure:
The carboxylic acid obtained as above (0.25 mmol) was coupled with 6-aminobenzothiazole (0.25 mmol) using HBTU employing general procedure D. The product, 2-(2-Trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide, was obtained as a light brown solid after purification by silica gel chromatography using DCM/methanol as eluent. MS: m/z 454 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH:1]1([CH2:7][N:8]2[CH2:11][CH:10]([CH2:12][O:13][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC1CN(CC2CCCCC2)C1
Product: O=[N+]([O-])c1ccc(OCC2CN(CC3CCCCC3)C2)cc1

Procedure:
In a manner similar to Preparation 2, react 1-cyclohexylmethyl-3-azetidinemethanol with 1-fluoro-4-nitrobenzene to obtain the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[C:18]([CH3:30])([CH3:29])[C:17]=2[CH:16]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[Br:14][C:15]1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][C:21]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)=[CH:22][CH:23]=3)[C:18]([CH3:30])([CH3:29])[C:17]=2[CH:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(I)cc21
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
Solvent: Cc1ccccc1
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccc4ccccc4c3)cc21
Reaction time: 8 h
Yield: 65.9 %

Procedure:
In argon atmosphere, a mixture of 13.91 g (80.9 mmol) of 2-naphthaleneboronic acid, 30.0 g (80.9 mmol) of 2-bromo-7-iodo-9,9-dimethylfluorene, 4.67 g (4.0 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of toluene, 200 ml of dimethoxyethane, and 122.36 g of a 2 M sodium carbonate aqueous solution was refluxed under stirring for 8 h and left standing overnight. After adding water, the mixture was stirred at room temperature for one hour. After filtration and extraction with toluene, the organic phase was washed with water and then with a saturated saline solution. After drying over sodium sulfate, the toluene was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 21.3 g (yield: 76.1%) of 2-bromo-9,9-dimethyl-7-(naphthalene-2-yl)-9H-fluorene.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(OCC)(=O)C.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>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][S:10]([CH3:9])(=[O:11])=[O:12])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: Clc1ccc(Cl)nn1
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: COCCOC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
To a round bottom flask was added 3,6-dichloropyridazine (20.1 mmole), 4-(methylsulfonylamino)phenylboronic acid (20.1 mmole), tetrakis(triphenylphosphine)palladium (1.00 mmole), 2M Na2CO3 (30 mL), and 1,2-dimethoxyethane (120 mL). The resulting reaction mixture was heated at 85 C for 22 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by biotage column chromatography eluting with 4:1 ethyl acetate to hexane mixture to afford N-(4-(6-chloropyridazin-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:22]=[CH:21]C(C(O)=O)=[CH:16][CH:15]=2)[S:12][CH:13]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:22]=[CH:21][C:1]([C:2]([Cl:4])=[O:3])=[CH:16][CH:15]=2)[S:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2nc(CCl)cs2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2nc(CCl)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (3.2 mL, 36.6 mmol, 5 eq.) was added dropwise to a suspension of 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoic acid (1.86 g, 7.32 mmol, 1 eq.) in DCM (10 mL) followed by a catalytic amount of DMF at RT. The reaction mixture was allowed to stir at RT overnight and then evaporated to give the title compound as the crude product.
Reaction SMILES: [C:1]([C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])[CH:13]=3)[C:8]=2[C:7]([N:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([NH:32]C(=O)OCC3C=CC=CC=3)[CH2:27]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C([O-])=O.[NH4+]>[Pd].CO>[NH2:32][C@@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:7]2[C:8]3[C:9]4[C:14](=[CH:13][C:12]([C:17]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[O:18])=[CH:11][CH:10]=4)[NH:15][C:16]=3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=2)[CH2:27]1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](NC(=O)OCc5ccccc5)C4)c23)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](N)C4)c23)CC1
Temperature: 75 °C
Yield: 122.4 %

Procedure:
A mixture of (R)-benzyl 1-(1-carbamoyl-7-(4-methylpiperazine-1-carbonyl)-9H-carbazol-4-yl)piperidin-3-ylcarbamate (Example 16-1, 80 mg, 0.141 mmol), 10% palladium on carbon (14.97 mg, 0.014 mmol) and ammonium formate (53.2 mg, 0.844 mmol) in methanol (8 mL) was flushed with nitrogen and heated at 75° C. for 1 h. The mixture was cooled to rt, diluted with methanol and filtered through a Celite pad. The filtrate was concentrated to provide (R)-4-(3-aminopiperidin-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a white solid (75 mg, 98%). 1H NMR (400 MHz, methanol-d4) δ 8.13 (d, J=8.13 Hz, 1H) 7.86 (d, J=8.35 Hz, 1H) 7.68 (s, 1H) 7.29 (d, J=9.67 Hz, 1H) 6.86 (d, J=8.35 Hz, 1H) 3.54-3.72 (m, 2H) 3.24-3.53 (m, 5H) 2.88 (s, 3H) 2.11-2.29 (m, 1H) 1.92-2.11 (m, 2H) 1.44-1.73 (m, 1H). Mass spectrum m/z 435.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][C@H:6]1[OH:21].[H][H].C(OCC)C>CO.[Pd]>[CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@H:6]1[OH:21]
Reactant: Cc1cccc(O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: Cc1cccc(O[C@H]2CCNC[C@H]2O)c1C
Yield: 67.8 %

Procedure:
A solution of cis-benzyl 4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate (5.0 g, 14.0 mmol) in methanol (60 ml) was added to 5% palladium on charcoal (500 mg) under an atmosphere of nitrogen. The vessel was placed under an atmosphere of hydrogen and stirred vigorously until hydrogen uptake ceased. The resulting suspension was filtered over a short pad of celite (pre-washed with methanol) and the pad washed with a further portion of methanol (150 ml). Concentration of the methanolic solution in vacuo gave a yellow oil. Dilution with diethyl ether (150 ml) yielded cis-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine as a white solid (2.1 g, 67%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12][C:3]=12.[Br:14]Br>Br>[BrH:14].[Br:14][CH:9]1[CH2:10][CH2:11][CH2:12][C:3]2=[N:2][CH:7]=[CH:6][CH:5]=[C:4]2[C:8]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCCCc2ncccc21
Agent: Br
Agent: Cl
Product: O=C1c2cccnc2CCCC1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 138 %

Procedure:
To a warm solution of 4.61 g (28.60 mmol) of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (Example 41) in 50 ml of 48% hydrobromic acid is added dropwise a solution of 5.00 g (31.28 mmol) of bromine in 10 ml of 48% hydrobromic acid. The solution is stirred at room temperature for 2 hours and then concentrated to an orange oil. Crystallization in 95% ethanol affords 6.93 g (75.5%) of 6-bromo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one, hydrobromide as a white solid; mp 193°-195° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)(=[O:36])=[O:35])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11o, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.66 (m, 1H), 7.96 (m, 1H), 7.85 (m, 2H), 7.68 (d, 1H), 7.50 (d, 2H), 7.46 (m, 1H), 7.16 (d, 2H), 7.09 (m, 1H), 6.99 (d, 1H), 6.92 (d, 1H), 6.88 (s, 1H), 6.43 (m, 1H), 4.48 (s, 2H), 4.44 (s, 2H), 3.63 (s, 3H), 2.78 (t, 2H), 2.48 (t, 2H); MS 491 (M+1).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:34]1[CH2:39][CH:38]=[C:37]([C:40]([CH3:44])([CH3:43])[CH:41]=O)[CH2:36][CH2:35]1.Cl>O1CCCC1.O>[O:34]1[CH2:39][CH:38]=[C:37]([C:40]([CH3:44])([CH3:43])[CH2:41][CH:2]=[O:3])[CH2:36][CH2:35]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)C1=CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CC=O)C1=CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
Step E To a mixture of methoxymethyl triphenylphosphonium chloride (31.3 g, 91 mmol) in anhydrous tetrahydrofuran (150 mL) at 0° C. was a tetrahydrofuran solution (Aldrich, 1 M) of LiHMDS (110 mL, 110 mmol) dropwise. After the addition was finished, the reaction mixture was stirred at 0° C. for 20 min. Then a tetrahydrofuran solution (40 mL) of 2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propionaldehyde (4.4 g, 28.5 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was dissolved into a solution of aqueous HCl solution (2 N, 50 mL, 100 mmol) and tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 30 min, then cooled to room temperature and concentrated. The residue partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give 3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-butyraldehyde as a brown oil (2.61 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:4]=1[NH2:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23].O>C(OCC)C>[CH3:12][O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:3]([O:2][CH3:1])[C:4]=1[NH:5][C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: COc1cc(C)cc(OC)c1NC(=O)CC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
8.2 g of 2,6-dimethoxy-4-methylaniline are dissolved in 100 ml of diethyl ether at 0° C. under an inert atmosphere, 5.96 g of triethylamine are added to the reaction mixture and then 6.51 g of isovaleryl chloride are added dropwise, while maintaining the temperature at 0° C. The mixture is left at room temperature for 30 minutes and is then poured into 250 ml of water. The aqueous phase is extracted with ethyl acetate after separation by settling of the ethereal phase. The organic phases are combined and washed with water, then dried over anhydrous sodium sulphate and evaporated to dryness. The white crystals of N-(2,6-dimethoxy-4-methylphenyl)isovaleramide obtained are washed with diisopropyl ether; M.p.=139° C., Yield: 92%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:18]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]2)(=[O:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=[O:13]
Reactant: CC1CCCNC1
Reactant: O=C(O)c1cc(Cl)cc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CC1CCCN(S(=O)(=O)c2cc(Cl)cc(C(=O)O)c2)C1

Procedure:
The procedure of Example 43 is repeated, starting with 5 g. (0.05 mole) of 3-methylpiperidine and 2.5 g. (0.01 mole) of 3-chloro-5-chlorosulfonylbenzoic acid in 15 ml. of methylene chloride, providing 2.7 g., m.p. 177°-179° C. of the crude product. Purification is effected by recrystallization from acetone-hexane, 1.2 g., m.p. 181°-183° C.
Reaction SMILES: [O:1]=[O+][O-].[C:4]([O:15][CH3:16])(=[O:14])[CH2:5][CH:6]([CH2:8][CH2:9][CH:10]=C(C)C)[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[CH:10]([CH2:9][CH2:8][C@@H:6]([CH3:7])[CH2:5][C:4]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: O=[O+][O-]
Reactant: COC(=O)CC(C)CCC=C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)C[C@H](C)CCC=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ozone generated by a Welsbach Ozonator was passed, at -78° C., into a solution of R(+) methyl citronellate (JACS 1968, 90, 3525; 3.0 g) in MeOH (30 mL) for 1.5 h. There was added more MeOH (60 mL) and triphenylphosphine (5.13 g, 1.2 eq.) and the mixture was stirred at room temperature for 45 min. The methanol was evaporated off, the residue was diluted with Et2O (100 mL) and the insoluble phosphine oxide filtered. The filtrate material was chromatographed on silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, to afford the compound as a colorless oil (1.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[S:9][C:10]3[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[S:9][C:10]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccc(Cl)cc3)sc2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(Cl)cc1)c1sc2cc(O)ccc2c1-c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 7 g. of the product from Example 18 and 27 g. of pyridine hydrochloride was refluxed in a 220° C. oil bath for 1.5 hours. The hot reaction mixture then was poured over an ice-water mixture. The resulting solid was collected and dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The ethyl acetate solution was evaporated, and the residue was recrystallized from methanol to give 3.59 g. of the title compound, m.p. 222° C.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[CH:24]1([CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:46]=[CH:45][C:44]([O:47]C)=[CH:43][C:40]=3[C:41]#[N:42])[CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:40]=3[C:41]#[N:42])[CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc(N2CCN(CCCC3CCCCC3)CC2)c(C#N)c1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: N#Cc1cc(O)ccc1N1CCN(CCCC2CCCCC2)CC1
Yield: 62.1 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 2-[4-(3-cyclohexylpropyl)piperazin-1-yl]-5-methoxybenzonitrile (430 mg), and the resulting crude product was purified on TLC (developer, chloroform: methanol=10:1) to provide 2-[4-(3-cyclohexylpropyl)piperazin-1-yl]-5-hydroxybenzonitrile (256 mg).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)=[O:15])[CH:11]=[CH:12][CH:13]=1.[I-].C[S+](C)C>CS(C)=O.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]([C:14]2([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[CH2:1][O:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(c1cccc(Br)c1)c1cccc(Br)c1
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Brc1cccc(C2(c3cccc(Br)c3)CO2)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
KOt-Bu (2.72 g, 24.26 mmol) was added to a stirred suspension of bis(3-bromophenyl)methanone (7.5 g, 22.06 mmol) and trimethylsulfonium iodide (4.50 g, 22.06 mmol) in DMSO (20 mL) and the resulting mixture was stirred at 30° C. for 8 h. The mixture was diluted with ethyl acetate (500 mL), washed with water (500 mL×3) and brine (500 mL). The organic layer was separated and evaporated in vacuo to afford the title compound which was used directly without further purification.
Reaction SMILES: C([O:8][C:9](=[O:22])[C@H](CCCNC(=N)N)N[N+]([O-])=O)C1C=CC=CC=1.N[C@H](C(O)=O)C.C([O:36][C:37](=[O:59])[C@H:38]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[NH:58])[NH2:57])[N:39]([N+]([O-])=O)[C:40](=[O:48])[CH:41]([CH3:47])[CH2:42]C(OC)=O)C1C=CC=CC=1.COC(CC(C)C(N[C@H](C(O)=O)CCCNC(=N)N)=O)=O>>[C:9]([CH:52]([CH2:53][CH2:54][NH:55][C:56](=[NH:58])[NH2:57])[C@@H:38]([C:37]([OH:36])=[O:59])[NH:39][C:40](=[O:48])[CH:41]([CH3:42])[CH3:47])([OH:22])=[O:8]
Reactant: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: COC(=O)CC(C)C(=O)N([C@@H](CCCNC(=N)N)C(=O)OCc1ccccc1)[N+](=O)[O-]
Agent: COC(=O)CC(C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: C[C@H](N)C(=O)O
Product: CC(C)C(=O)N[C@H](C(=O)O)C(CCNC(=N)N)C(=O)O

Procedure:
By substituting nitro-L-arginine benzyl ester for the L-alanine in the procedure of Example 1, and then treating the product by the procedures of Examples 2 and 3, Nα -(3-methoxycarbonyl-2-methylpropanoyl)-nitro-L-arginine benzyl ester, Nα -(3-methoxycarbonyl-2-methylpropanoyl)-L-arginine and Nα -(3-carboxy-2-methylpropanoyl-L-arginine are obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[Cl:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: NCc1ccc(Cl)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Br)c2)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (1,000 mg, 2.210 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (487 mg, 2.210 mmol), HBTU (1,006 mg, 2.65 mmol) and Et3N (1.540 mL, 11.05 mmol) in DCM was stirred at room temperature over the weekend. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). The product fractions were combined to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1,100 mg, 41%). LC-MS m/z 654.4 (M+H)+, 0.93 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=O)=[CH:5]2.[NH2:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)=[O:18]>>[CH2:24]([C@H:16]([NH:15][C:12]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[F:11])=[O:14])[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2[nH]1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSC1)c1cc2cc(F)cc(F)c2[nH]1

Procedure:
From 5,7-difluoro-1H-indole-2-carboxylic acid and (S)-2-amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one. mp 175-185° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>C(OCC)C.Cl.[NH4+].O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([OH:12])([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(CBr)cc1
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)N1CCC(O)(Cc2ccc(C)cc2)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A solution of 1-ethoxycarbonyl-4-piperidone (39 ml, 0.26 mol) in diethylether (150 ml) was added dropwise at room temperature to a solution prepared from 4-methyl-benzylbromide (237 g, 1.28 mol) and Mg (31.2 g, 1.28 mol) in diethylether (300 ml). Room temperature was maintained for 45 min with stirring and the mixture was then refluxed for 5 h. It was cooled to 0° C., diluted with diethylether (700 ml) and hydrolyzed with saturated ammoniumhydrochloride solution (200 ml) and water (350 ml). Insoluble material was removed by filtration over Celite", the residue washed twice with diethylether (2×500 ml) and the organic phase was separated. The water layer was extracted with diethylether, the organic phases were pooled and dried with MgSO4 and the solvent evaporated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 2:1) to give 4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-carboxylic acid ethylester (70.5 g, 99%) as a yellowish oil, MS: m/e=278 (M+H+).