Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18](C)([C:22](O)=O)[C:19]([OH:21])=[O:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)(C(=O)O)c1ccc2nc(-c3ccc(Cl)cc3)ccc2c1
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc2nc(-c3ccc(Cl)cc3)ccc2c1

Procedure:
10 g of 2-(p-chlorophenyl)-α-methyl-6-quinolinemalonic acid are heated to 190°C for 20 minutes. The melt is cooled and dissolved in ethyl acetate, and the solution is extracted with 0.5 N sodium carbonate solution. The sodium carbonate extracts are adjusted to pH 5 and extracted with ethyl acetate. The ethyl acetate extracts, on evaporation and recrystallisation of the residue from ethyl acetate-petroleum ether, yield 2-(p-chlorphenyl)-α-methyl-6-quinolineacetic acid of melting point 188°-189°C.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>[Fe].C(O)(=O)C>[NH2:1][C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2nc(-c3cccnc3)oc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cccc2nc(-c3cccnc3)oc12
Temperature: 25 °C

Procedure:
4 ml of 10% acetic acid was added to 7-nitro-2-(3-pyridyl)benzoxazole prepared in Reference Example 3, and 200 mg of powdered iron was added by portions with stirring at room temperature. The mixture was heated to 100° C. in an oil bath and stirred for 2 hr. The reaction mixture was filtered through Celite and washed with a small amount of dilute hydrochloric acid. The filtrate was neutralized with an aqueous sodium hydroxide solution, the product was extracted with ethyl acetate, and the organic layer was dried. The organic solvent was removed by evaporation to provide 153 mg of the intended title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: OCc1cnc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cnc(N2CCNCC2)c(Cl)c1

Procedure:
A mixture of 5,6-dichloro-3-pyridinemethanol (0.71 g, 4 mmol, TCI-US), piperazine (0.52 g, 6 mmol) and N,N-diisopropylethylamine (1 mL, 5.8 mmol, Aldrich) was reacted under the conditions of Example 43a to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 228 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[CH3:38][N:36]([CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([O:19][C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:40][CH:39]=3)[CH:25]=[CH:24][N:23]=2)=[O:28])[CH2:34][CH2:33]1)[CH3:37]
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 30 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (79 mg) and (+)-10-camphorsulfonic acid (49.7 mg) in ethanol (3.0 ml) at room temperature, the mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=4:1) to provide the title compound (36.5 mg, 30%) as white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[CH2:11][C:10]=2[CH:26]=1.[Cl-].CC1(C)CCCC(C)(C)[N+]1=[O:37].CC(=CC)C.[O-]Cl=O.[Na+]>C(Cl)Cl.O.CCOC(C)=O>[C:2]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[CH2:11][C:10]=2[CH:26]=1)([OH:37])=[O:1]
Reactant: CCOC(=O)CC1=Cc2ccc(CCCCO)cc2Cc2ccccc21
Reactant: CC1(C)CCCC(C)(C)[N+]1=O
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC1=Cc2ccc(CCCC(=O)O)cc2Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of ethyl (±)-3-[4-hydroxy-1-butyl]-5H-dibenzo[a,d]cycloheptene-10-acetate (342.4 mg, 0.97 mmole) in anhydrous CH2Cl2 (19 mL) was cooled to 0° C. under argon, and 2,2,6,6-tetramethyloxopiperidinium chloride (J. Org. Chem. 1985, 50, 1332-1334; 260 mg, 1.36 mmole) was added in one portion. The reaction was stirred at 0° C. for 1 hr, then 2-methyl-2-butene (1.2 mL, 11 64 mmole) was added, followed by a cold (0° C.) solution of NaClO2 (0.88 g, 7.76 mmole) and NaH2PO4 (0.90 g, 6.50 mmole) in H2O (26 mL). After 10 min, the reaction was diluted with EtOAc (100 mL) and the layers were separated. The organic layer was washed sequentially with cold 1.0 N HCl (10 mL) and saturated brine (20 mL), dried (MgSO4), and concentrated. Silica gel chromatography (gradient: 1:1 EtOAc/CHCl3 then 9:9:2 EtOAc/CHCl3 /EtOH) gave impure title compound. Rechromatography on silica gel (7:3:0.1 toluene/EtOAc/AcOH) gave the pure title compound (233.7 mg, 66%): TLC (1:1 EtOAc/CHCl3) Rf 0.46; 1H NMR (400 MHz, CDCl3) δ 7.05-7.22 (m, 4 H), 6.92-7.05 (m, 3 H), 4.34 (d, J=15.0 Hz, 1 H), 4.10-4.25 (m, 2 H), 3.80-3.90 (m, 2 H), 3.33 (dd, J=15.1, 4.1 Hz, 1 H), 2.95 (dd, J=15.1, 9.4 Hz, 1 H), 2.48-2.60 (m, 4 H), 2.48-2.60 (m, 4 H), 2.37 (t, J=7.4 Hz, 2 H), 1.87-2.00 (m, 2 H), 1.27 (t, J=7.2 Hz, 3 H); MS (ES) m/e 389 (M+Na)+, 367 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19]([NH2:20])=[N:18][C:16]2=[O:17])[C@H:12]([OH:23])[C@:11]1([C:25]#[CH:26])[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:33])[CH2:29][C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19]([NH:20][C:30](=[O:31])[CH2:29][N:28]([CH3:33])[CH3:27])=[N:18][C:16]2=[O:17])[C@H:12]([OH:23])[C@:11]1([C:25]#[CH:26])[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C#C[C@@]1(O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc(N)nc2=O)[C@@H]1O
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C#C[C@@]1(O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc(NC(=O)CN(C)C)nc2=O)[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Compound 1 (1.9 g, 5 mmol), N,N-dimethylglycine (1.0 g, 10 mmol), N,N-dimethylaminopyridine (0.1 g, 0.8 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.9 g, 10 mmol) were added to DMF (20 mL) under ice-cooling, and the mixture was stirred for one day at 40° C. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL) and saturated brine (50 mL), and then dried over magnesium sulfate. Magnesium sulfate was removed through filtration, and the filtrate was concentrated. The residue was purified through silica gel chromatography (4% methanol/chloroform solvent mixture). The eluate was concentrated, and the residue was recrystallized from hexane, to thereby yield Compound 17 (0.46 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([C:11]=1[CH:12]=[N:13]O)=[CH:9][CH:8]=[CH:7][CH:6]=2>N.[Ni]>[NH2:13][CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:3][C:2]=1[Cl:1]
Reactant: ON=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Agent: [Ni]
Agent: N
Product: NCc1c(Cl)nc(-c2ccccc2)c2ccccc12
Reaction time: 0.5 h
Yield: 21 %

Procedure:
12.5 g 3-Chloro-1-phenyl-isoquinoline-4-aldoxime are hydrogenated in 500 ml of methanolic ammonia in the presence of 30 g of prehydrogenated Raney-nickel, at room temperature and under atmospheric pressure. After 30 minutes, the precipitate is filtered off from the catalyst, the solution is concentrated and the residue is chromatographed on 200 g of silica gel using a mixture of chloroform and methanol (8:2). 2.5 g 4-Aminomethyl-3-chloro-1-phenyl-isoquinoline having a melting point from 101° to 103° C. are isolated.
Reaction SMILES: N1CC(=O)NC1=O.[C:8]1([C:14]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:18][C:17](=[O:19])[N:16]([CH2:20][OH:21])[C:15]2=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:29][CH:30]([CH3:34])[C:31](Cl)=[O:32]>C(OCC)C>[Br:29][CH:30]([CH3:34])[C:31]([O:21][CH2:20][N:16]1[C:15](=[O:22])[C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:18][C:17]1=[O:19])=[O:32]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reactant: CC(Br)C(=O)Cl
Agent: O=C1CNC(=O)N1
Solvent: CCOCC
Product: CC(Br)C(=O)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidine-dione imidazolidinedione (2 g, 0.0071 tool) was dissolved in 2-bromopropionyl chloride (8.5 g, 5 ml, 0.05 mol) by heating for 30 minutes on a 100°-110° C. oil bath. The reaction mixture was cooled, 20 ml of ethyl ether were added, and the resultant solution was extracted with aqueous potassium carbonate, dried and then crystallized. The product was obtained as a solid white substance (1 g, 34% ), m.p. 112°-115° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.77; H, 4.15; N, 6.69; Br, 19.25. The product has the formula: ##STR1524##
Reaction SMILES: C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:9][S:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[CH:15]=[N:14]1)(=[O:12])=[O:11].[CH2:23]([N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][C:29](=O)[CH2:30]2)[CH2:24][CH3:25].[OH-].[Na+]>CO>[CH3:9][S:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][CH:29]3[CH2:28][CH:27]4[N:26]([CH2:23][CH2:24][CH3:25])[CH:31]([CH2:32][CH2:33]4)[CH2:30]3)=[CH:19][CH:20]=2)[CH:15]=[N:14]1)(=[O:11])=[O:12]
Reactant: CS(=O)(=O)n1ncc2cc(N)ccc21
Reactant: CCCN1C2CCC1CC(=O)C2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1C2CCC1CC(Nc1ccc3c(cnn3S(C)(=O)=O)c1)C2
Temperature: 25 °C
Reaction time: 96 h
Yield: 2.9 %

Procedure:
Sodium cyanoborohydride (242 mg, 3.85 mmol) and then acetic acid (220 μl, 3.84 mmol) were added to a solution of 1-(methylsulfonyl)-1H-indazol-5-amine (163 mg, 0.772 mmol) and 8-propyl-8-azabicyclo[3.2.1]octan-3-one (150 mg, 0.924 mmol) in methanol (3 ml), and the resulting mixture was stirred at room temperature for 4 days. A 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified successively by a silica gel column chromatography (chloroform/methanol=4/1), a preparative thin-layer chromatography (200×200×0.5 mm, 2 plates, eluent: chloroform/methanol=4/1) and partition by LC/MS (water containing 0.05% trifluoroacetic acid-acetonitrile containing 0.035% trifluoroacetic acid, 10%–100% gradient, the extraction of the organic layer with aqueous ammonia/ethyl acetate after the partition) to obtain 1-(methylsulfonyl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (8 mg, 3%).
Reaction SMILES: S(O)(O)(=O)=O.[N:6]1[C:10]2[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=2[NH:8][CH:7]=1.S(Cl)(Cl)=O.Cl[CH2:23][CH2:24]Cl>>[N:6]1([C:15]([CH:13]2[CH2:12][CH2:11][C:10]3[N:6]=[CH:7][NH:8][C:9]=3[CH2:14]2)=[O:17])[C:23]2[C:24](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Reactant: ClCCCl
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: O=C(C1CCc2nc[nH]c2C1)N1CCc2ccccc21
Temperature: 30 °C
Yield: 82.7 %

Procedure:
4,5,6,7-Tetrahydrobenzimidazole-5-carboxylic acid sulfate (1.32 g) was refluxed in 10 ml of 1,2-dichloroethane together with 1.78 g of thionyl chloride for 30 minutes, and the excess of thionyl chloride and the solvent were removed by distillation under reduced pressure. To the residue was added ml of 1,2-dichloroethane, and 1.6 ml of indoline was added dropwise thereto at 30° C. or lower while stirring followed by stirring at room temperature for 2 hours. The reaction mixture was successively extracted once with 30 ml of water and twice with 20 ml of water. The combined aqueous layer was adjusted to a pH of 9 to 10 with a 10% sodium hydroxide aqueous solution and then extracted with methylene chloride. The combined methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.1 g (82.7%) of 5-[(2,3-dihydroindol-1-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: C(O)(=O)C.I[CH:6]([CH2:17][C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(O)C.[Zn]>[F:25][C:20]([F:26])([C:21]([F:22])([F:23])[F:24])[C:19]([F:27])([F:28])[C:18]([F:30])([F:29])[CH2:17][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: OCCCCCCCCCC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a slurry of 130.0 g of zinc powder in 500 mL of ethanol was added 5.0 g of acetic acid. A solution of 230.0 g of the crude 10-iodo-11-(nonafluorobutyl)-1-undecanol prepared above in 100 mL of ethanol was added dropwise with stirring over 1 hr. Then, the reaction mixture was heated at 50° C. for 4 hr. The mixture was filtered, and the filtrate was concentrated to a viscous, light yellow liquid. Bulb-to-bulb distillation of the liquid, in several portions, provided 97.3 g of 11-(nonafluorobutyl)-1-undecanol as a colorless solid, b.p. 160-200° C. at 0.05 torr (7 Pa).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3]C(C)(C)C)=[O:2].C(N(C(C)C)CC)(C)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([OH:3])=[O:2])[CH2:13][CH2:12]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 1-Boc-piperazine (0.50 g, 2.7 mmol) and diisopropylethylamine (1.75 g, 13.5 mmol) in dichloromethane at 0° C. was added a solution of 2-trifluoromethylbenzoyl chloride (0.626 g, 3.0 mmol). The resulting mixture was stirred at room temperature for 20 h and then quenched with water (25 mL). The organic phase was washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 4-(2-trifluoromethylbenzoyl)piperazine-1-carboxylic acid tent-butyl ester as a pale brown oil (0.948 g, 98% yield). 1H NMR (300 MHz, CDCl3) δ 7.69, 7.54, 7.30, 3.77, 3.51, 3.33, 3.14, 1.45.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[C:14]#[N:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1cc(F)ccc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
In a 12 L, 4-neck round bottom flask equipped with a mechanic stirrer and temperature probe, a suspension of sodium hydride (74 g, 1.82 mol) in DMF (1.95 L) was added benzyl alcohol (142 g, 1.3 mol) through a dropping funnel slowly over 30 minutes in an ice bath under nitrogen. The mixture was stirred in an ice bath (0° C.) for 120 minutes, a solution of 2,5-difluorobenzonitrile (180 g, 1.3 mol) in DMF (650 mL) was added through a dropping funnel over 35 minutes. The resulting mixture was warmed up to room temperature. After 2 hours, the mixture was cooled in an ice bath (4° C.) and quenched with saturated NH4Cl (130 mL) followed by the addition of water (2.6 L×3). The slurry was stirred at room temperature overnight and the precipitate was filtered and washed with water (650 mL×3). The solid was dried in vacuum for 2 days to give 292 g (99.3%) of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, 1H, J=3.2 Hz, J=8.2 Hz), 7.5-7.76 (m, 1H), 7.35-7.48 (m, 6H), 5.28 (s, 2H).
Reaction SMILES: [CH:1]1[N:16]2[C:17]3[C:8]([C:9](=[O:18])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=42)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:19])[N:2]=1>O>[CH2:1]1[N:16]2[C:17]3[C:8]([C:9](=[O:18])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=42)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:19])[NH:2]1
Reactant: O=c1ncn2c3ccccc3c(=O)c3cccc1c32
Solvent: O
Product: O=C1NCn2c3ccccc3c(=O)c3cccc1c32

Procedure:
Prepared from compound 4 (X=O, R=H) according to General Procedure A (0.16 g, 80%). Yellow solid, mp 250-255° C. MS: (M−1): 249; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, br, 1H), 8.46 (d, 1H), 8.39-8.32 (m, 2H), 7.90-7.86 (m, 2H), 7.45-7.40 (m, 2H), 5.71 (s, 2H); 13C NMR (100 MHz, DMSO-d6) 176.39, 161.78, 140.87, 139.92, 134.94, 133.49, 131.41, 127.25, 122.81, 122.13, 121.77, 121.22, 118.39, 115.78, 56.46; Anal. (C15H10N2O2. 0.36 H2O). C H N.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([F:34])=[C:8]2[C:12]([C:13](=[O:33])[C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[N:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:11][NH:10][C:9]=12)(=O)[CH3:2].Cl.[NH2:36][OH:37]>CCO>[F:34][C:7]1[CH:6]=[N:5][C:4](/[C:1](=[N:36]/[OH:37])/[CH3:2])=[C:9]2[NH:10][CH:11]=[C:12]([C:13](=[O:33])[C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[N:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[C:8]=12
Reactant: CC(=O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Reactant: NO
Agent: Cl
Solvent: CCO
Product: C/C(=N\O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C

Procedure:
To a suspension of 1-(7-acetyl-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.05 g, 0.11 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (0.04 g, 0.58 mmol). The mixture was heated to reflux for 1 h, and was then cooled to rt, and concentrated in vacuo. The residue was diluted with MeOH, and the solids that formed were collected and washed with water. The title compound was isolated as an off-white solid (0.027 g). LCMS: m/e 478.5 (M+H)+, ret time 1.53 min (method 1). 1H NMR (500 MHz, DMSO-D6) δ ppm 11.95 (s, 1 H) 11.61 (s, 1 H) 8.34 (d, J=1.83 Hz, 1 H) 8.30 (d, J=3.36 Hz, 1 H) 7.56-7.71 (m, 5 H) 3.68-3.72 (m, 2 H) 3.43-3.48 (m, 2 H) 3.30-3.34 (m, 2 H) 3.13-3.17 (m, 2 H) 2.35 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]2[C:18]([I:27])=[N:19][N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:14]=2[CH:13]=1.S(Cl)([Cl:31])(=O)=O>C(Cl)Cl>[Cl:31][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:12]1[N:17]=[CH:16][C:15]2[C:18]([I:27])=[N:19][N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:14]=2[CH:13]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
At r.t. to a solution of 6-(2-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (35 mg, 0.072 mmol) (Example 52, Step 4) in methylene chloride (3 mL) was added sulfuryl chloride (7.0 μL, 0.087 mmol). The mixture was stirred at r.t. for 20 min then concentrated. The solid was filtered out and the crude material was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.025 g). LCMS (M+H)+=518.1.
Reaction SMILES: B.C1CCCCC=1.[NH:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:31]([C@@:34]([C:43]([NH2:45])=[O:44])([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35])[CH:32]=[CH2:33].OO>C1COCC1.C(O)C>[NH:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH:12][CH2:33][CH2:32][CH2:31][C@@:34]([C:43]([NH2:45])=[O:44])([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35]
Reactant: C=CC[C@](N)(Cc1ccccc1)C(N)=O
Agent: B
Agent: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: OO
Solvent: C1CCOC1
Solvent: C1=CCCCC1
Solvent: CCO
Product: NC(=O)[C@](N)(CCCO)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of borane in THF (1.44 mL of a 1M solution, 1.44 mmol) at 0° C. under nitrogen, was added cyclohexene (0.29 mL, 2.88 mmol) by syringe, and the mixture was stirred for 0.5 hour, during which time a white precipitate formed. A prechilled (0° C.) solution of t-BOC-Asp(OBn)-α-allylphenylalaninamide (480 mg, 0.92 mmol), from Step e, in anhydrous THF (4 mL) was added and stirring was continued for 2 hours at 0° C., then at ambient temperature overnight. The solution was diluted with pH 7 buffer and ethanol and treated with excess 30% aqueous H2O2 and stirred overnight. The reaction mixture was then partitioned between ethyl acetate and brine and the aqueous phase was extracted with two portions of ethyl acetate. The ethyl acetate solutions were combined, dried over anhydrous sodium sufate, filtered and concentrated. The residue (514 mg) was chromatographed on silica gel eluting with hexane/acetone (1:1) to give 266 mg (54% yield) of the title compound (1:1 diastereomeric mixture) as a colorless solid, m.p. 75°-79° C.; 1H NMR (CDCl3) δ1.37 (s) and 1.40 (s) (total of 9H), 1.50-1.71 (m,2H), 1.92-2.12 (m) and 2.13-2.27 (m) (total 2H), 2.21-2.38 (overlapping dd's,J=6 and 18 Hz and J=5 and 16 Hz,total 2H), 3.10 (dd,J=4.5 and 17 Hz,2H), 3.25-3.48 (m,2H), 3.61 (m,2H), 4.60 (m,1H), 5.10 (s) and 5.12 (s) (total 2H), 5.32 (br m,1H), 5.45 (br t,J=9 Hz,1H), 6.42 (br m,1H), 7.12 (m,2H), 7.16-7.40 (m,8H). MS (DCl/NH3) m/e 528 (M+H)+, 545 (M+NH4)+ . Analysis calculated for C28H37N3O7.0.1H2O: C, 63.52; H, 7.08; N, 7.94. Found: C, 63.21; H, 7.03; N, 7.68.
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]([CH3:20])[CH:6]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=O)[CH2:7][C:8]([O:10][CH3:11])=[O:9].O>C(O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]([CH3:20])=[N:2][NH:3][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NN
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccn1
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1c(C)n[nH]c1-c1ccccn1

Procedure:
1.170 g (23 mmol) of hydrazine hydrate were added to a solution of 5 g (21 mmol) of methyl 4-oxo-3-(pyridin-2-ylcarbonyl)pentanoate in ethanol (50 ml). The mixture was heated at reflux for 7 hours, added to water and extracted with ethyl acetate. The combined organic phases were dried with magnesium sulfate, filtrered and concentrated. This gave 2.290 g of product (41.9% of theory).