Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)=[CH:3][CH:2]=1>C(O)C.[OH-].[Na+].O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12]3([CH2:19][CH2:18][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15]3)[CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2
Temperature: 70 °C

Procedure:
To a solution of 0.05 g (0.145 mmol) of the ester from Example 22 in 2 ml ethanol were added three drops of 2N aqueous sodium hydroxide solution. The mixture was heated at 70° C. for 3 h and diluted with 10 ml water. It was washed two times with dichloromethane, and the aqueous layer was adjusted to pH 7-8 with hydrochloric acid. After another extraction with dichloromethane the aqueous layer was concentrated under reduced pressure and the residue stirred with 20 ml of a mixture of ethanol/dichloromethane 9:1. Solids were removed by filtration, and the filtrate was concentrated in vacuo to leave the pure title acid.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:22]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:22])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: N
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1

Procedure:
Boil (under reflux) 5 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde together with 7.6 g of activated manganese dioxide and 300 ml of toluene with the introduction of ammonia using a water-trap. Filter after 5 hours and then evaporate the filtrate to dryness in vacuo before recrystallizing three times from dimethylformamide and water to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile [m.p. 190° to 192° C].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:13])[C:10](C#N)=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[C:24]([N:28]1[C:2]2[N:7]3[N:8]=[C:9]([C:13]4[CH:16]=[CH:15][CH:3]=[CH:4][CH:14]=4)[CH:10]=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: Cc1nc2c(C#N)c(C)nn2c(Cl)c1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3ccccc3)nn2c2c1CCN2C(C)(C)C
Yield: 70.1 %

Procedure:
A mixture of 16.11 g of Compound (VI) [R2 =H, R3 =H], 38 g of anhydrous potassium carbonate, 5.85 g of tert-butylamine, and 140 ml of dimethylformamide was heated at 50°-60° C. in a water bath for 2 days while stirring. The reaction mixture was cooled and filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in 150 ml of chloroform. The chloroform layer was washed with water and evaporated under reduced pressure to obtain 15.72 g of an oily substance. The oily substance was purified using silica gel chromatography, followed by recrystallizing in a mixed solvent of benzene-isopropylether-hexane to produce 8-tert-butyl-6,7-dihydro-5-methyl-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine [R1 =C(CH3)3, R2 =H, R3 =H in formula (I)] (Compound 11 of this invention) as light yellow plate crystals having a melting point of 147°-149° C. at a yield of 70.1%.
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]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[NH3:22].O>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([NH2:22])=[O:15]
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Reactant: N
Solvent: O
Solvent: CCOCC
Product: CC(OCc1ccc2ccccc2c1)(C(N)=O)C(F)(F)F

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (1.3 g.) in ether (10 ml.) is added to a mixture of ammonia (d, 0.90; 10 ml.) and water (100 ml.). The mixture is shaken, and the ether is evaporated. The solid is filtered off and crystallised from light petroleum (b.p. 100°-120° C.) to give (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionamide (0.76 g.) m.p. 111°-112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH2:21])=[S:20]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:21]=[CH:19][S:20][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC=S
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Solvent: CCO
Product: c1ccc(COc2ccc(-c3cscn3)cc2)cc1
Temperature: 0 °C
Yield: 27.4 %

Procedure:
A mixture of 4'-benzyloxy-2-bromoacetophenone (3.0 g) and thioformamide (0.63 g) in ethanol (50 ml) was refluxed under heating for 30 minutes. The reaction mixture was poured into ice-water, and the precipitating crystals were collected by filtration, extracted with diethyl ether and purified by column chromatography on silica gel [eluting solvent: methylene chloride-hexane (1:9)] to give 4-(4-benzyloxyphenyl) thiazole (720 mg, 27.7%), which was further purified by recrystallization from diethyl ether-hexane. m.p. 109°-110° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O:9][C:10](=O)[CH2:11][C:12]#[N:13])C>C(OCC)(=O)C>[C:12]([CH2:11][C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:9])#[N:13]
Reactant: C1COCCN1
Reactant: CCOC(=O)CC#N
Solvent: CCOC(C)=O
Product: N#CCC(=O)N1CCOCC1
Temperature: 105 °C
Yield: 701.7 %

Procedure:
A 4-neck 500 mL flask was charged with morpholine (77.0 g, 0.088 mol). Ethylcyanoacetate (100.0 g, 0.088 mol) was added. After addition, the reaction mixture was stirred. The mixture progressively turned yellow to clear. The mixture was heated to 100 to 110° C. for 3.0 hours. A solid formed after cooling to room temperature. Ethyl acetate (150 ml) and heptanes (300 ml) were added and the mixture stirred for 30 minutes at room temperature. The solid was filtered to give 95.2 g (71% yield) of 4-cyanoacetylmorpholine. 1H NMR: δ (DMSO-d6) 4.02 (s, 2H); 3.37 (m, 2H); 3.55 (m, 4H); 3.45 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.[NH4+].[Cl-]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.00 g; 2.93 mmol) and K2CO3 (1.30 g; 9.41 mmol) in DMF (40 mL) was added ethyl bromoacetate (1.50 g; 8.98 mmol). The mixture was stirred at 70° C. for 2 hours, cooled to r.t., diluted with 10% aqueous NH4Cl (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.10 g (88%) of the title compound as a yellow solid, which was used directly without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][N:13]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:15]3)=[N:9]2)=[CH:4][CH:3]=1.[O:22]1[CH2:26][CH2:25][NH:24][C:23]1=[O:27].C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[CH:18]1([N:13]2[CH2:14][CH2:15][C:16]3=[CH:17][N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:24]5[CH2:25][CH2:26][O:22][C:23]5=[O:27])=[CH:3][CH:4]=4)[N:9]=[C:10]3[CH2:11][CH2:12]2)[CH2:21][CH2:20][CH2:19]1
Reactant: Brc1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1OCCN1c1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-(4-bromophenyl)-6-cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Example 35) (42 mg, 0.12 mmol), 2-oxazolidinone (21 mg, 0.24 mmol), potassium carbonate (50 mg, 0.36 mmol), copper (I) iodide (8.0 mg, 0.04 mmol) and N,N′-dimethyl-1,2-ethanediamine (5 μl, 0.04 mmol) in dioxane (1.5 ml) was heated in the microwave (high absorption) at 100° C. for 30 minutes. The same amounts again of 2-oxazolidinone, potassium carbonate, copper (I) iodide and N,N′-dimethyl-1,2-ethanediamine were added and the mixture heated in the microwave at 150° C. for 4 hours. The reaction mixture was evaporated in vacuo, then purified by SCX cartridge, followed by Mass Directed Autopreparation to afford the title compound (E37). MS (ES+) m/e 353 [M+H]+.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][O:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH:13]1[NH:17][CH2:16][CH2:15][S:14]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([N:17]1[CH2:16][CH2:15][S:14][CH:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=1[O:8][CH3:7])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: COc1ccccc1OCC1NCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OCC1SCCN1C(=O)C(C)Br
Reaction time: 1 h

Procedure:
α-Bromopropionylchloride (0.97 ml) in methylene chloride (15 ml) is added dropwise to a mixture of 2-(o-methoxyphenoxy)methyl-thiazolidine (2 g) and triethylamine (1.35 ml) in CH2Cl2 (30 ml) at 0°-5° C. After 1 hour, the mixture is washed with water and the usual work-up gives 3-α-bromopropionyl-2-(o-methoxyphenoxy)methyl-thiazolidine as a colourless oil.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=3)=[N:13][CH:12]=[CH:11][N:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:23]([N:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[C:32]([CH3:38])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>ClC(Cl)C.C(=O)(O)[O-].[Na+].CO.C(O)(=O)C>[ClH:1].[CH2:23]([N:30]1[C:34]([CH3:35])=[C:33]([CH2:36][N:6]2[CH2:7][CH2:8][N:3]([C:9]3[C:14]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=4)=[N:13][CH:12]=[CH:11][N:10]=3)[CH2:4][CH2:5]2)[C:32]([CH3:38])=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: Cc1nn(Cc2ccccc2)c(C)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1nn(Cc2ccccc2)c(C)c1CN1CCN(c2nccnc2-c2ccc(CO)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
Combine [4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-phenyl]-methanol dihydrochloride (0.210 g, 0.612 mmol), 1-benzyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde (0.131 g, 0.612 mmol) and triethylamine (0.171 mL, 1.22 mmol) in dichloroethane (5 mL). Add glacial acetic acid (50 μL) followed by sodium triacetoxyborohydride (0.181 g, 0.856 mmol). Stir at room temperature for 3 days. Dilute with saturated aq. sodium bicarbonate then extract three times using DCM. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 4.5:95.5 methanol (with 2 M ammonia):DCM), to give a yellow oil. Dissolve the oil in methanol and add ammonium chloride (1 equivalent) then sonicate the mixture for 10 min. Evaporate the solution to give the title compound as a yellow solid (0.241 g, 78%). MS (ES): m/z=469
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:43][N:44]1[CH:48]=[CH:47][N:46]=[C:45]1[CH:49]=O>CO>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:49][C:45]2[N:44]([CH3:43])[CH:48]=[CH:47][N:46]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)C(=O)OC(C)(C)C
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h
Yield: 71.1 %

Procedure:
The compound (231 mg) obtained in Example 76-4 was dissolved in anhydrous methanol (5.0 ml) and added with sodium cyanoborohydride (61.6 mg), acetic acid (2.00 ml), and 1-methyl-2-imidazole carboxaldehyde (80.9 mg). The whole was stirred at room temperature for 6 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (197 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)c(OC)c(OC)c3)cccc2c1N
Yield: 88.7 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3,4,5-trimethoxyphenyl boronic acid (206 mg, 0.97 mmol) were reacted to afford the title compound (116 mg, 91.5% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.80 (dd, J=7.2 Hz, J′=1.4 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 6.87 (s, 2H), 3.92 (s, 3H), 3.90 (s, 6H), 3.47 (q, J=6.5 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=397 (M+H) HPLC 1.83 min.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[OH-:15].[Na+].II>O.C(O)C>[O:15]=[C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])[CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)CCS)C1
Reactant: [OH-]
Agent: II
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1C[C@@H](C(=O)O)N(C(=O)CCSSCCC(=O)N2CC(=O)C[C@H]2C(=O)O)C1

Procedure:
The product from Example 2 is dissolved in water and the pH adjusted to 6.5 by the addition of 1 N sodium hydroxide. To this stirred solution is added dropwise a 0.5 M iodine solution in 95% ethanol (6.34 g. iodine/50 ml. solution) while maintaining the pH at 5.5 to 6.5 with 1 N sodium hydroxide. Excess iodine is removed with dilute sodium thiosulfate and the solution is concentrated, cooled and acidified with 1:1 hydrochloric acid. Solvent is added and the layers are separated. The organic layer is dried (MgSO4) and the solvent evaporated to yield as a residue 1,1'-[dithiobis(1-oxo-3,1-propanediyl)]bis[4-oxo-L-proline].
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:45])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][C@H](N)[CH2:40][CH2:39]2)=[O:36])[CH:12]=[CH:13][CH:14]=1.[S:46]([NH2:50])([NH2:49])(=[O:48])=[O:47]>C1COCC1>[Cl:8][C:9]1[C:10]([F:45])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][CH:38]2[CH2:43][CH2:42][N:49]([S:46]([NH2:50])(=[O:48])=[O:47])[CH2:40][CH2:39]2)=[O:36])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N[C@H]2CC[C@H](N)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: NS(N)(=O)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCN(S(N)(=O)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 110 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexylamine trifluoroacetic acid salt (50 mg, 0.091 mmol) in THF (3 mL), sulfamide (Aldrich, 40 mg, 0.416 mmol) was added and the mixture was stirred at 110° C. for 25 min. on microwave oven. The reaction was quenched with addition of water. The mixture was extracted with EtOAc (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (25-90, acetonitrile/water) to give a white solid. 49 mg.
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]([C:8]2[C:12]([CH:13]=[CH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][NH:10][N:9]=2)[NH:6][CH:7]=1.[OH-].[NH4+:24]>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[CH:13][C:12]2[C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:2]#[N:24])[N:4]=3)=[N:9][NH:10][CH:11]=2)[CH:16]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1c[nH]c(-c2n[nH]cc2C=Cc2cccnc2)n1
Agent: [OH-]
Product: N#Cc1c[nH]c(-c2n[nH]cc2C=Cc2cccnc2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 3-{2-[3-(4-trifluoromethyl-1H-imidazol-2-yl)-1H-pyrazol-4-yl]-vinyl}-pyridine Compound 2 (50 mg, 0.164 mmole) and 5% aqueous ammonium hydroxide (20 mL) was stirred at 60° C. for 3 h until all of the starting material disappeared. After the solvent was removed in vacuo, the residue was dissolved in methanol and neutralized with several drops of 2M aqueous HCl to pH˜7. The solvent was evaporated and the crude compound was diluted with ethyl acetate and washed with water. The organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by flash chromatography with 10% methanol/dichloromethane to give 2-[4-(2-pyridin-3-yl-vinyl)-1H-pyrazol-3-yl]-1H-imidazole-4-carbonitrile Compound 3 as a white solid (21.5 mg, 50%). 1H NMR (300 MHz, MeOD) δ 7.10 (d, J=16.5 Hz, 1H), 7.44 (dd, J=5, 7.8 Hz, 1H), 7.82 (d, J=14 Hz, 1H), 7.92 (s, 1H), 8.09 (d, J=7.7 Hz 1H), 8.18 (s, 1H), 8.37 (dd, J=1.5, 5 Hz, 1H), 8.63 (d, J=2 Hz, 1H); MS (ESI) m/z: 263.7 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CCOC(=O)C1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 37.7 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.0 g (2.6 mmol) and 4-amino-cyclohexanecarboxylic acid ethyl ester (0.48 g, 2.6 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.34 (5H, m), 1.41 (5H, m), 1.92 (4H, m), 2.1 (1H, t), 3.81 (1H, m), 4.12 (2H, q), 7.04 (4H, dd), 7.51 (2H, s), 7.89 (3H, d), 8.41 (1H, d). Percentage purity (HPLC): 89.3%.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)#[N:2].C([Sn]([N:28]=[N+:29]=[N-:30])(CCCC)CCCC)CCC.Cl>COCCOC.CO>[NH:28]1[C:1]([CH2:3][C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[N:2][N:30]=[N:29]1
Reactant: CCOC(=O)c1ccc(CC#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: COCCOC
Solvent: CO
Product: CCOC(=O)c1ccc(Cc2nnn[nH]2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Ethyl 4-cyanomethylbenzoate (approximately 8 g) was dissolved in DME (10 ml). The solution was added tris(n-butyl)tin azide (5 ml) and the resultant solution was stirred and heated at 85° C. overnight. The solution was cooled to room temperature. The cooled solution was diluted with methanol then acidified with 1N hydrochloric acid. The acidified mixture was stirred for one hour then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cncc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cncc(C)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (370 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a pale-yellow oil (yield 256 mg, 88%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (78 mg) in ethanol (2 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 288 mg, 87%).