Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](N)[CH:10]=[C:11](S(O)(=O)=O)[C:12]=3[OH:17])[C:7](=[O:23])[C:6]=2[C:5](N)=[CH:4][C:3]=1S(O)(=O)=O.[OH-:29].[Na+].S(S([O-])=O)([O-])=[O:32].[Na+].[Na+]>>[CH2:3]1[C:2](=[O:1])[C:15]2[C:6](=[C:7]([OH:23])[C:8]3[C:13]([C:14]=2[OH:16])=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[OH:32])[C:5](=[O:29])[CH2:4]1
Reactant: [OH-]
Reactant: Nc1cc(S(=O)(=O)O)c(O)c2c1C(=O)c1c(N)cc(S(=O)(=O)O)c(O)c1C2=O
Reactant: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: O=C1CCC(=O)c2c1c(O)c1c(O)ccc(O)c1c2O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The 1,8-dihydroxy-4,5-diaminoanthraquinone-2,7-disulfonic acid reaction mixture prepared as in Example 5c, was cooled to 70°C. It was then treated with 117 parts of 50% sodium hydroxide solution and 70 parts of sodium hydrosulfite. The mixture was heated to 78° to 100°C and held at that temperature for 1 hour. It was then cooled to 60°C and filtered. The product was washed with dilute sodium sulfate solution containing about 1% of sodium hydrosulfite and the washed cake was immediately slurried in 10 to 15% sulfuric acid. The filtration of the product and drying yielded 20 parts of leuco 1,4,5,8-tetrahydroxyanthraquinone.
Reaction SMILES: [NH2:1][C:2]([CH2:4][NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:3]>CO>[C:14]1([C:13]2[N:5]([CH2:4][C:2]([NH2:1])=[O:3])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)CNc1ncccc1NC(=O)c1ccccc1
Solvent: CO
Product: NC(=O)Cn1c(-c2ccccc2)nc2cccnc21
Yield: 45 %

Procedure:
A 7.62-g (0.028 mole) sample of N-[2-[[(aminocarbonyl)methyl]-amino]-3-pyridinyl]benzamide was heated in glass in a Wood's metal bath under a flow of nitrogen at 200° C. for 7 minutes. The green solid residue was broken up with a glass rod in methanol and the solid was filtered off. The filtrate was concentrated and the precipitate which formed, was separated by filtering twice. The solids were combined and recrystallized from boiling water to give 3.19 g (45%) of white needles which were dried under high vacuum at room temperature overnight, mp. 226°-7° C.
Reaction SMILES: CC(=C)C.[CH3:5]/[CH:6]=[C:7](/[CH:9]=[CH:10]/[CH:11]=[C:12]([CH3:14])[CH3:13])\[CH3:8].[CH3:15]C(=CC=CC(C)=CC)C.[C:25](=[O:28])(O)[O-].[Na+]>>[CH3:25][O:28][C:12]([C:11]1[CH:5]=[CH:6][C:7]([CH:8]=[CH2:15])=[CH:9][CH:10]=1)([CH3:14])[CH3:13]
Reactant: C/C=C(C)/C=C/C=C(C)C
Reactant: CC=C(C)C=CC=C(C)C
Reactant: O=C([O-])O
Agent: C=C(C)C
Agent: [Na+]
Product: C=Cc1ccc(C(C)(C)OC)cc1

Procedure:
The following examples show that conjugated diene units can also be incorporated in butyl elastomers by carbocationic copolymerization with isobutylene. Technical grade (80%) alloocimene, (2,6-dimethyl-2,4,6-octatriene) of 95.6% actual purity level which was purchased from Aldrich and dried by column chromatography using aluminum oxide (neutral, Brockmann I activity (Aldrich) and degassed by freeze-pump-thaw technique. Isobutylene (IB), 99% purity and methyl chloride (MeCl), 99.5% purity (Matheson TRIGAS) were condensed from gas phase after drying it by passing through a column filled with BaO/CaCl2. Hexane(s) (Mallinckrodt Chemicals with 98.5% minimum purity) was freshly distilled off CaH2 (Aldrich). Di-tert-butylpyridine (DtBP, 97%, TIC), N,N-Dimethyl acetamide (DMA, 99.8%, anhydrous, Aldrich) and titanium tetrachloride (TiCl4, 99.9%, Aldrich) were used as received. p-Vinylcumyl methyl ether (inimer) was synthesized based on the procedure described in (C. Paulo, J. E. Puskas, Macromolecules 2001, 34, 734-739). It was purified by column chromatography using neutral Brockmann activity I alumina (Aldrich) and n-pentane. 2-Chloro-2,4,4-trimethylpentane (TMPCl) was made by hydrochlorination of 2,4,4-trimethylpent-1-ene (TMP-1, Acros). After completion of the reaction, solution was neutralized by the slow addition of sodium bicarbonate, dried over CaH2 and filtered. It was degassed with freeze-pump-thaw cycles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC[C@@H](C(O)=O)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)OCc2ccccc2)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 192, starting from (R)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)#[N:25].Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:34])=[CH:30][CH:31]=1)#[N:25]
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 4-Cyanophenyl isocyanate (34 mg, 0.24 mmol) was added and the reaction mixture was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 28 (60 mg, 64% yield) as a yellow solid. LC-MS (M+H=353, obsd.=353).
Reaction SMILES: Cl[CH:2]([Cl:23])[B:3]1[O:7][C:6]([CH2:9][CH2:10][CH:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:8])[C:5]([CH3:22])([CH3:21])[O:4]1.[CH2:24]([Mg]Br)[CH3:25]>O1CCCC1.C(OCC)(=O)C>[Cl:23][CH:2]([B:3]1[O:7][C:6]([CH2:9][CH2:10][CH:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])([CH3:8])[C:5]([CH3:21])([CH3:22])[O:4]1)[CH2:24][CH3:25]
Reactant: CC(CCC1(C)OB(C(Cl)Cl)OC1(C)C)CC(=O)OC(C)(C)C
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(Cl)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -78 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
0.86 g (2.3 mmol) of tert-butyl 5-[2-(dichloromethyl)-4(RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 5 ml of tetrahydrofuran and the solution was cooled to -78° C. under a nitrogen atmosphere. 2.6 ml (2.6 mmol) of 1M ethylmagnesium bromide in tetrahydrofuran were added dropwise, the resulting solution was stirred for 16 hours while slowly warming to room temperature and then diluted with ethyl acetate and extracted with 2M hydrochloric acid and brine. The organic phase was dried over sodium sulphate and then evporated under a vacuum to give 0.83 g of tert-butyl 5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1 ,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in the next step without purification.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:49])[C@H:6]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([C:41]2[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:48])=[O:40])=[CH:34][CH:33]=1)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)=[N:19][N:18]=[N:17]2)=[CH:12][C:11]=1[Cl:30])=[O:9]>CO.C1COCC1.O>[Cl:47][C:46]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:48])[C:41]=1[C:39]([NH:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][C@@H:6]([C:5]([OH:49])=[O:4])[NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=4)=[N:19][N:18]=[N:17]3)=[CH:12][C:11]=2[Cl:30])=[O:9])=[CH:37][CH:36]=1)=[O:40]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
An aqueous 1N lithium hydroxide solution (0.33 mL) was added to a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]phenyl]carbonyl]-L-phenylalanine methyl ester (75 mg; 0.108 mmol) in methanol (0.66 mL) and THF (0.66 mL) and the mixture was stirred at room temperature for 90 min. After the solvents were stripped under reduced pressure, the residue was dissolved in water (20 mL) and extracted with diethyl ether (3×5 mL). The aqueous layer was filtered through Celite, then acidified with 1 N HCl (0.35 mL). The resulting colorless solid was filtered off, washed with water, and dried in vacuo to give 57 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]phenyl]carbonyl]-L-phenylalanine. FAB HRMS: (C31H24Cl3N7O5) Obs. Mass 680.0981 Calcd. Mass 680.0983 (M+H).
Reaction SMILES: [Br-].[CH3:2][N+:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[I:11][CH2:12][CH2:13][CH2:14]I>C(#N)C>[I-:11].[I:11][CH2:12][CH2:13][CH2:14][N:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH3:10])([CH3:9])[CH3:2])[CH3:8]
Reactant: ICCCI
Reactant: CNCCC[N+](C)(C)C
Agent: [Br-]
Solvent: CC#N
Product: CN(CCCI)CCC[N+](C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 216.2 mg. (1 mmole) of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 1.5 ml. of acetonitrile is added a solution of 296 mg. (1 mmole) 1,3-diiodopropane in 0.5 ml. of acetonitrile. The mixture is stirred at room temperature for 2.0 hours and the insoluble N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide hydrobromide is removed by filtration. The filtrate is evaporated and the solid residue obtained is extracted with methylene chloride. The methylene chloride extract is evaporated to give the oily product which is recrystallized from isopropanol-ether.
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=O)=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]#[N:18])=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Yield: 96.3 %

Procedure:
From 1.3 g (0.0048 mol) of 2-ethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxamide (Example 22), 30 ml of phosphorus oxychloride and 30 ml of chloroform and refluxing on a steam bath for six hours, following the procedure of Example 27, there is obtained 1.18 g of 2-ethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carbonitrile; mp 223°-224° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.[Br:7][CH:8]([CH:11]=O)[CH:9]=O>C(O)(=O)C.CO>[Br:7][C:8]1[CH:9]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:11]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1ccn[nH]1
Solvent: CO
Solvent: CC(=O)O
Product: Brc1cnc2[nH]ncc2c1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
1H-Pyrazol-5-amine (5.3 g, 64 mmol) and 2-bromomalonaldehyde (9.9 g, 64 mmol) were suspended in acetic acid (100 mL). The reaction mixture was heated to reflux under N2 for 6 hours. The reaction mixture was cooled to room temperature and concentrated to give a solid. The crude solids were suspended in MeOH (200 mL) and absorbed onto silica gel (200 g). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 5-bromo-1H-pyrazolo[3,4-b]pyridine as a solid (3.1 g, 25%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:40]([N:47]1[CH2:51][CH2:50][C@H:49]([C:52](O)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:40]([N:47]1[CH2:51][CH2:50][C@H:49]([C:52]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)[C@H]1CCN(Cc2ccccc2)C1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)[C@H]1CCN(Cc2ccccc2)C1
Yield: 21.8 %

Procedure:
This compound was prepared according to method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.181 g; 0.476 mmol), (S)-1-benzylpyrrolidine-3-carboxylic acid hydrochloride (0.119 g; 0.476 mmol), and N,N-diisopropylethylamine (0.189 mL; 1.08 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of a solution of 5% ammonium hydroxide in methanol, in dichloromethane) to afford 0.036 g (22%) of (S)-1-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [ClH:1].[N:2]1([C:7]([NH2:9])=[NH:8])[CH:6]=[CH:5][CH:4]=N1.Cl.Cl.[N:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=CC(CN)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>CO>[OH2:28].[ClH:1].[N:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:28])[C:20]2[CH:21]=[CH:22][C:5]([CH2:6][NH:2][C:7]([NH2:9])=[NH:8])=[CH:4][CH:25]=2)=[CH:14][CH:13]=1
Reactant: N=C(N)n1cccn1
Reactant: NCc1ccc(C(=O)Nc2ccncc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCc1ccc(C(=O)Nc2ccncc2)cc1
Product: O
Temperature: 25 °C
Reaction time: 6 h
Yield: 112.3 %

Procedure:
Pyrazole-1-carboxamidine hydrochloride (540 mg) was added to a solution of N-(4-pyridyl)-4-aminomethylbenzamide dihydrochloride (550 mg) and diisopropylethylamine (950 mg) in methanol (7 ml), and the mixture was stirred in a stream of nitrogen at room temperature for 6 hours. After the reaction, the reaction mixture was concentrated to half under reduced pressure, and ethyl acetate was added to precipitate crystals. The crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give 333 mg of N-(4-pyridyl)-4-guanidinomethylbenzamide monohydrochloride monohydrate having a melting point of 244-248° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[NH:8][C:7](C(O)=O)=[C:6]([CH2:14][CH3:15])[C:5]=2[C:4](=[O:16])[CH2:3]1.O>C(O)(=O)C.Cl>[CH3:17][C:2]1([CH3:1])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:14][CH3:15])[C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: CCc1c(C(=O)O)[nH]c2c1C(=O)CC(C)(C)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A suspension of 6,6-dimethyl-3-ethyl-4-oxo-4,5,6,7-tetrahydro- 1H-indole-2-carboxylic acid (2.5 g, 0.011 mol) in acetic acid (12 mL) and hydrochloric acid (10M; 0.64 mL) was heated at 100° C. for 45 min. After this time water (50 mL) was added, the cooling bath removed and the solution stirred at room temperature for 2 h. The precipitate was collected by filtration and the title pyrrole (1.76 g, 87%) isolated as a colourless solid. mp. 150° C.-152° C. C12H17NO requires: C, 75.35; H, 8.96; N, 7.32%. Found: C, 75.00; H, 8.88; N, 7.24%. 1H NMR (250 MHz, CDCl3) δ 1.10 (6H,s), 1.19 (3H,t,J=7.4 Hz), 2.32 (2H,s), 2.63 (2H,s), 2.75 (2H,d of q,J=7.4 and 1.0 Hz), 6.42 (1H,br s), 8.00 (1H,br s). MS (ES+) 192 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=O.[CH:23]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH4-].[Na+].O>CO>[CH:23]1([CH2:28][CH2:29][NH:30][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:5][CH:4]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCC1CCCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)c3ccccc23)nc1
Reaction time: 16 h

Procedure:
To a solution of 6-(4-formylnaphthalen-1-yloxy)nicotinamide (Preparation 2) (200 mg, 0.7 mmol) in MeOH (10 mL) was added 2-cyclopentyl ethylamine (116 mg, 1.0 mmol) and 4 Å molecular sieves (200 mg). The mixture was stirred for 16 h before adding NaBH4 (130 mg, 3.4 mmol). After 1.5 h water (1 mL) was added and the mixture filtered. Solvent was removed in vacuo and the residue purified by column chromatography (0.5% NH3: 2% MeOH:DCM) to give the title compound: RT=2.68 min; m/z (ES+)=390.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]#[N:20])[CH:13]=2)[N:5]=1)=[O:3].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N=[C:31]=[N:32][CH:33]([CH3:35])[CH3:34])(C)C.Cl>CN(C=O)C>[C:19]([C:14]1[CH:13]=[C:12]([N:6]2[C:7]([C:9]([N:21]3[C:23]4[C:24](=[CH:35][C:33]([N:32]5[CH2:31][CH2:9][CH2:7][CH2:8][CH2:4][C:2]5=[O:3])=[CH:34][CH:22]=4)[CH2:25][CH2:26]3)=[O:11])=[CH:8][C:4]([C:2]([NH2:1])=[O:3])=[N:5]2)[CH:17]=[CH:16][C:15]=1[F:18])#[N:20]
Reactant: c1ccncc1
Reactant: N#Cc1cc(-n2nc(C(N)=O)cc2C(=O)O)ccc1F
Reactant: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-n2nc(C(N)=O)cc2C(=O)N2CCc3cc(N4CCCCCC4=O)ccc32)ccc1F
Reaction time: 1 h
Yield: 49 %

Procedure:
Part B. To the product from Part A (95 mg, 0.41 mmol), was added 3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid (94 mg, 0.34 mmol), 3.3 mL of pyridine, and 0.70 mL of DMF. 1,3-Diisopropylcarbodiimide (0.059 mL, 0.38 mmol) was added, and the resulting solution was stirred for 1 h. The red mixture was then poured into 1N aqueous HCl (70 mL) and washed with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. Concentration of the filtrate and purification of the resulting residue by radial chromatography (1-5% MeOH in CH2Cl2) gave 1-(3-cyano-4-fluorophenyl)-5-{[5-(2-oxo-hexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide (98 mg, 49%) as a brown residue. LC/MS (ESI+): 487.1 (M+H)+. 1H NMR (CD3OD) δ 8.08 (br m, 1H), 7.97 (br d, 1H), 7.87 (br s, 1H), 7.43 (br t, 1H), 7.28 (s, 1H), 7.12 (br s, 1H), 7.00 (br d, 1H), 4.24 (br m, 2H), 3.73 (br s, 2H), 3.16 (br m, 2H), 2.66 (br s, 2H), 1.79 (br s, 6H).
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:11]2[CH:33]=[C:34]([CH3:38])[C:35]([CH3:37])=[CH:36][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:11]2[CH:33]=[C:34]([CH3:38])[C:35]([CH3:37])=[CH:36][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2nc(Cc3ccccc3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2nc(Cc3ccccc3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1C

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-benzyl-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].O.[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[CH2:19][C:18]1([CH3:32])[CH3:33])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH3:43])[CH3:39])([CH3:10])([CH3:11])[CH3:9]
Reactant: CC(C)(C)CN
Reactant: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3c(F)cccc3F)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: O
Product: C[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2c(F)cccc2F)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
8 mg of 2-hydroxypyridine (0.083 mmol) was added to a solution of 200 mg of {(S)-2-[4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (93b) (0.42 mmol) in (2,2-dimethylpropyl)amine (1 ml), and the mixture was stirred at 80° C. for six hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=40/1-20/1) to obtain 221 mg of the title compound (yield: 94%).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[C:10](=O)[C:11]3[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[NH:25]C(=O)C(F)(F)F)=[CH:13][CH:14]=[N:15][C:16]=3[C:17](=[O:18])[C:8]=2[N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][N:7]=[C:8]2[C:9]=1[C:10]1[N:25]=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[C:12]3[CH:13]=[CH:14][N:15]=[C:16]([C:11]=13)[C:17]2=[O:18])([O-:3])=[O:2]
Reactant: O=C1c2nccc(-c3ccccc3NC(=O)C(F)(F)F)c2C(=O)c2c([N+](=O)[O-])ccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2nccc([N+](=O)[O-])c2-c2nc3ccccc3c3ccnc1c23
Reaction time: 8 h
Yield: 49.8 %

Procedure:
365 mg (0.826 mmol) of the compound of Example 3 and 2 mL of trifluoroacetic acid in 20 mL of CH2Cl2 are refluxed for 3 hours. After evaporating off the solvent on a rotary evaporator, the residue is taken up in 20 mL of 1N NaOH and 20 mL of CHCl3 and the reaction medium is stirred overnight. The organic phase is recovered and the aqueous phase is extracted with CHCl3 (5 times 20 mL). After drying the organic phases over MgSO4 and evaporating off the solvent on a rotary evaporator, the residue is purified by flash chromatography on a column of RP8 grafted silica (60/40 MeOH/H2O) to give 135 mg of compound in the form of pale orange-yellow crystals.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:20]([O:22][C:23](=[O:36])[CH:24]([O:33][CH2:34][CH3:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:22][C:23](=[O:36])[CH:24]([O:33][CH2:34][CH3:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:14][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)[CH:27]=1)[CH3:21]
Reactant: CS(=O)(=O)Oc1ccc(CCCCS(=O)(=O)[O-])cc1
Reactant: CCOC(=O)C(Cc1cccc(O)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Yield: 64.6 %

Procedure:
3-(4-Methanesulfonyloxyphenyl)propylmethanesulfonate (1.905 g; 6.18 mmole) dissolved in acetonitrile (13 ml) was added dropwise to a mixture of 2-ethoxy-3-(3-hydroxyphenyl)propanoic acid ethyl ester (1.47 g; 6.18 mmole) and potassium carbonate (2.56 g; 18.54 mmole) in acetonitrile (15 ml). The mixture was refluxed for 5 hours, then the solvent was evaporated in vacuo and water was added. The mixture was extracted twice with dichloromethane, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using diethyl ether/petroleum ether (gradient 33% to 100% diethyl ether) gave 1.80 g (yield 65%) of 2-ethoxy-3-{3-[3-(4-methanesulfonyloxyphenyl)propoxy]phenyl}propanoic acid ethyl ester.