Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15]([OH:18])(=O)=[O:16])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15]([Cl:20])(=[O:18])=[O:16])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)O)cccc12
Product: CC(=O)Nc1cccc2c(S(=O)(=O)Cl)cccc12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
1.40 g of 5-acetylaminonaphthalene-1-sulfonic acid and 2.23 g of phosphorus pentachloride are combined and stirred for 4 hours at 60° C. Then the solution is poured onto ice water and extracted with dichloromethane. The organic extracts collected are dried with sodium sulfate and evaporated down in vacuo. Yield: 1.10 g.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][OH:35])=[O:16])[CH2:6][CH2:5]2
Reactant: NCCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCO)O2
Yield: 48.3 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 357 mg CDI (2.20 mmol) and 165 mg 3-aminopropanol (2.2 mmol) produced 297 mg of 6-hydroxy-N-(3-hydroxypropyl)-2,5,7,8-tetramethylchroman-2-carboxamide as an amorphous white solid.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:41](=[O:43])[CH3:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[N:32]=[C:31]2[C:30](=[CH:29][CH:28]=1)[N:33]=[CH:34][C:35]([C:41](=[O:43])[CH3:42])=[C:36]2[OH:38]
Reactant: CCOC(=O)C(=CNc1ccc(Cl)nc1)C(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1O
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To a flask containing Dowtherm™ A (500 mL) at 250° C. was added ethyl 2-[(6-chloropyridin-3-ylamino)methylene]-3-oxobutanoate (10 g, 27 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and dried under vacuum to afford the intermediate 1-(6-chloro-4-hydroxy-1,5-naphthyridin-3-yl)ethanone which was heated in neat phosphorus oxychloride with catalytic N,N-dimethylformamide for 4 h at 70° C. The reaction was cooled and poured slowly into a vigorously stirring mixture of ice-cold satd. aq. sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to provide the desired product (3 g, 46% over two steps) as a brown solid: ESI MS m/z 241 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[CH:21]=[C:20]1I)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1.[Li]CCCC>C1COCC1>[C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[CH:21]=[C:20]1[F:40])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)O[C@@H]2[C@@H](C=C(I)[C@@H]2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](C=C(F)[C@@H]2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Tert-butyl((3aR,4R,6aR)-5-iodo-2,2-dimethyl-4,6a-dihydro-3H-cyclopenta[d][1,3]dioxol-4-yloxy)diphenylsilane (5-4) (1.4 g, 2.7 mmol, 1 equiv) was dissolved in dry THF (18 mL) and N-fluorobenzenesulfonimide (1.0 g, 3.2 mmol, 1.2 equiv) was added. The resulting mixture was cooled to −78° C. and BuLi (3.2 mL, 8.0 mmol, 3 equiv, 2.5 M in hexanes) was added dropwise over 10 minutes. The mixture was stirred at the same temperature for 1 hour. Upon disappearance of the starting material, the reaction was quenched with the addition of 20 mL NH4Cl, extracted with EtOAc (3×20 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (80 g SiO2, 0-50% EtOAc in hexanes) to yield tert-butyl((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)diphenylsilane (5-5) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J=5 Hz, 2H); 7.75 (d, J=6.5 Hz, 2H); 7.35-7.44 (m, 6H); 5.27 (s, 1H); 4.77 (dd, J=6.0, 2.0 Hz, 1H); 4.39 (t, J=6.0 Hz, 1H); 4.46 (td, J=6.0, 2.0 Hz, 1H); 1.52 (s, 3H); 1.35 (s, 3H); 1.10 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][CH:3]=1>[Ru]>[CH3:1][CH:2]1[C@H:7]2[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC1=CCC2CC1C2(C)C
Agent: [Ru]
Product: CC1CC[C@H]2C[C@@H]1C2(C)C

Procedure:
Ruthenium has been found to be a stereoselective catalyst for the hydrogenation of α-pinene to obtain cis-pinane.
Reaction SMILES: [C:1]([CH:6]([NH:15][C@H:16]([C:18]([CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]([C:30]([OH:32])=[O:31])[NH:21]1)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3]CC)=[O:2].[OH-].[Na+].Cl>O1CCOCC1.O>[C:1]([CH:6]([NH:15][C@H:16]([C:18]([CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]([C:30]([OH:32])=[O:31])[NH:21]1)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)C1NC(C(=O)O)Cc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)C1NC(C(=O)O)Cc2ccccc21
Reaction time: 1 h

Procedure:
880 mg of N-(1-carboethoxy-3-phenylpropyl)-L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are dissolved in 20 ml of dioxane/water (9:1) and are hydrolyzed at room temperature with 4.5 ml of 1N sodium hydroxide solution. After one hour, the solution is acidified with the equivalent quantity of 1N hydrochloric acid, and the dioxane is largely evaporated off. The residue is extracted several times with ethyl acetate, and, after the solvent has been stripped off, the organic phase is subjected to chromatography over a cation exchanger (DOWEX 50). Yield: 630 mg
Reaction SMILES: [Mg:1].II.[Br:4]C1CC1.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:10]1([Mg:1][Br:4])[CH2:11][CH2:12]1.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [Mg]
Reactant: BrC1CC1
Agent: II
Solvent: C1CCOC1
Product: Br[Mg]C1CC1
Reaction time: 1.5 h

Procedure:
Magnesium (10.7 g) was suspended in tetrahydrofuran (80 ml), and to the suspension was added iodine (5 mg). Bromocyclopropane (32.0 ml) was added dropwise thereto over 1.5 hr and the mixture was heated under reflux for 1.5 hr. Thereto was added tetrahydrofuran to give a 1M cyclopropylmagnesium bromide-tetrahydrofuran solution. Subsequently, o-anisaldehyde (8.17 g) was dissolved in tetrahydrofuran (150 ml), the 1M cyclopropylmagnesium bromide-tetrahydrofuran solution (90 ml) was added dropwise thereto over 50 min under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, a saturated aqueous ammonium chloride solution (9 ml) was added, and the reaction mixture was stirred at room temperature for 30 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give the title compound (6.13 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][CH:4]=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:7]1([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: Cn1nccc1C1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nccc1C1=CCCCC1
Yield: 87.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 99b by using the 1-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (11.32 g, 62.8 mmol) prepared in Example 123a, p-toluenesulfonic acid monohydrate (17.9 g, 94.1 mmol) and toluene (100 mL), to yield the title compound (8.89 g, 87%) as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.[H-].[Na+].Cl>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:37]\[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.4 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (28.0 g), tetraethyl methylenediphosphonate (17.5 g) and N,N-dimethylformamide (300 mL) was added sodium hydride (60% in oil, 2.43 g) at 0° C. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, 2N hydrochloric acid was added to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (2:3, v/v) to give diethyl (Z)-2-(3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as a colorless oil (1.94 g, yield 5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Zn]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([NH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 6-(benzyloxy)-3-nitropyridin-2-amine (J. Med. Chem. 1997, 40, 1808) (22.67 g, 92.44 mmol) in AcOH (300 mL) was added zinc dust (24.18 g, 369.7 mmol) in four portions over 10 min while cooling in an ice bath. The mixture was then allowed to warm to room temperature and stirred for 2 h. The mixture was filtered and the solvent was removed under reduced pressure. The product was taken up in EtOAc and washed with saturated NaHCO3 solution and brine. The organics were dried over MgSO4, filtered and concentrated to yield the title compound as a black solid (19.31 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.13 (s, 2H), 5.14 (s, 2H), 5.39 (s, 2H), 5.86 (d, J=7.9 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 7.28 (m, 1H), 7.34 (t, J=7.6 Hz, 2H), 7.40 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26](O)=[O:27])=[CH:23][CH:24]=3)[CH:19]=[N:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:41][CH2:42][CH:43]([NH:48][S:49]([C:52]1[C:57]([CH3:58])=[CH:56][C:55]([O:59][CH2:60][CH2:61][CH2:62][C:63](=[O:89])[NH:64][CH2:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][CH2:77][NH:78][C:79]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:80])=[CH:54][C:53]=1[CH3:90])(=[O:51])=[O:50])[C:44]([O:46][CH3:47])=[O:45].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:58][C:57]1[CH:56]=[C:55]([O:59][CH2:60][CH2:61][CH2:62][C:63](=[O:89])[NH:64][CH2:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][CH2:77][NH:78][C:79]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:80])[CH:54]=[C:53]([CH3:90])[C:52]=1[S:49]([NH:48][CH:43]([CH2:42][NH:41][C:26]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:9]1[N:8]([C:7]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=[CH:11][N:10]=1)[N:18]=[CH:19]2)=[O:27])[C:44]([O:46][CH3:47])=[O:45])(=[O:51])=[O:50]
Reactant: COC(=O)C(CN)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCCOCCOCCOCCCNC(=O)OCc2ccccc2)cc1C
Reactant: O=C(O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CNC(=O)c1ccc2c(cnn2CCCNc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCCOCCOCCOCCCNC(=O)OCc2ccccc2)cc1C

Procedure:
A solution of 1-(3-((1-(triphenylmethyl)imidazol-2-yl)amino)propyl)-1H-indazole-5-carboxylic acid, methyl 3-amino-2-(((2,6-dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)propanoate, DIEA, and HBTU in anhydrous DMF are stirred at ambient temperatures under nitrogen for 4 h. The DMF is removed under vacuum and the resulting residue is dissolved in EtOAc and washed with water, saturated NaHCO3, and saturated NaCl. The EtOAc layer is dried (MgSO4) and concentrated to dryness. The crude product is purified by flash chromatography on silica gel using EtOAc/MeOH.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1cnccc1C
Reactant: BrCCCc1ccccc1
Product: CCc1cnccc1CCCCc1ccccc1
Yield: 87.7 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 3.0 g (15.1 mmol) of 1-bromo-3-phenylpropane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 3.17 g of the desired compound (yield: 87.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[NH:8][C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:10][C:6]=2[CH:5]=1)([O-])=O>[Ni].CO>[N:12]1([CH2:11][C:9]2[NH:8][C:7]3[CH:17]=[CH:18][C:4]([NH2:1])=[CH:5][C:6]=3[N:10]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc2[nH]c(CN3CCCC3)nc2c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc2[nH]c(CN3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
1.00 g Raney nickel is added to a solution of 5.50 g (22.3 mmol) 5-nitro-2-pyrrolidin-1-ylmethyl-1H-benzimidazole in 50 mL MeOH. The reaction solution is stirred for 30 h at 3 bar H2 and RT. After filtration the solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:12]=[CH:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][CH:22]=[CH2:21])[C:6]([O:8][CH3:9])=[O:7])[CH:13]=[CH2:14]
Reactant: CC=Cc1cc(C(=O)OC)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1CC=C
Yield: 87 %

Procedure:
A solution of 3.04 g (15.8 mmol) of methyl 4-hydroxy-3-propenylbenzoate (Example 42, Step B) was refluxed with anhydrous potassium carbonate (4.37 g, 2 equiv) and allyl bromide (3.5 mL, 2.5 equiv) in acetone overnight. The mixture was filtered through Celite and the filter cake was washed with more acetone and dichloromethane. After removing the solvents, the resulting oil was distilled under high vacuum to give 3.2 g (87%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[N:35](C)[N:34]=[N:33][N:32]=4)[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1.[C:37]([O-])(=O)/C=C/C([O-])=O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[N:32]=[N:33][N:34]([CH3:37])[N:35]=4)[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCc4nnnn4C)CC2)cn3-c2ccc(F)cc2)n1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Product: Cn1nnc(CCN2CC=C(c3cn(-c4ccc(F)cc4)c4ccc(-c5nnn(C)n5)cc34)CC2)n1

Procedure:
Yield 0.9 g of 1-(4-fluorophenyl)-5-(2-methyltetrazol-5-yl)-3-[1-[2-(1-methyltetrazol-5-yl)-ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole, fumarate (17b). Mp 171-173° C. (ethanol). 1H NMR (DMSO-d6): δ 2.55-2.65 (m, 4H), 2.80 (t, 2H), 2.90 (t, 2H), 3.15 (t, 2H), 3.30 (broad s, 2H), 4.05 (s, 3H), 4.45 (s, 3H), 6.25 (broad s, 1H), 6.60 (s, 2H), 7.45 (t, 2H), 7.60-7.70 (m, 3H), 7.80 (s, 1H), 7.90 (d, 1H), 8.60 (s, 1H); MS m/z (%): 485 (MH+, 35), 346 (27), 140 (100).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([C:27]2[CH:35]=[CH:34][C:30]([C:31]([Cl:33])=[O:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[ClH:33].[C:21]1([C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[O:32])=[CH:34][CH:35]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1ccc(-c2ccccc2)cc1
Yield: 61.3 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.89 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 1.08 ml (4.98 mmol) of 4-phenylbenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 980 mg of the desired compound (free base) (67.8%, pale yellow powder), mp: 169.0°-170.0° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[S:17]([N:20]2[CH2:40][CH2:39][C:23]3([N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)[NH:25][C:24]3=[O:38])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[C:11]([CH3:41])[CH:10]=1.[H][H]>CCO.CN(C=O)C.[Pd]>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([N:20]2[CH2:21][CH2:22][C:23]3([N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=4)[NH:25][C:24]3=[O:38])[CH2:39][CH2:40]2)(=[O:19])=[O:18])=[C:11]([CH3:41])[CH:10]=1
Reactant: Cc1cc(N2C(=O)CC[C@@H]2CO)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(C(F)(F)F)c1)NC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(N2C(=O)CC[C@@H]2CO)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cccc(C(F)(F)F)c1)NC2=O
Yield: 45.1 %

Procedure:
8-{(E)-2-[4-((R)-2-Hydroxymethyl-5-oxo-pyrrolidin-1-yl)-2-methyl-phenyl]-ethenesulfonyl}-2-(3-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (28.5 mg, 48.3 μmol) was dissolved in EtOH/DMF 4:1 (concentration 10 mg/ml). The mixture was allowed to pass through 10% Pd/C (CatCart™) at a flow rate of 2 ml/min under the conditions of 30 bar and 40° C. in a hydrogen atmosphere, and was subjected to hydrogenation reaction. The resulting reaction solution was concentrated under reduced pressure. The residue was purified by preparative TLC(CH2Cl2/MeOH=20:1) to give 8-{2-[4-((R)-2-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-2-methyl-phenyl]-ethanesulfonyl}-2-(3-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a white powder (12.9 mg, 45%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[CH:12][CH:11]=2)[CH:6]=[C:5]([CH3:20])[N:4]=1>Cl>[ClH:1].[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7]2[CH:6]=[C:5]([CH3:20])[N:4]=[C:3]([NH2:2])[N:8]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1ccc(Nc2cc(C)nc(N)n2)cc1
Agent: Cl
Product: Cc1cc(Nc2ccc(N)cc2)nc(N)n1
Yield: 99.3 %

Procedure:
To a suspension of 16 (6.0 g, 20 mmol) was added 2N HCl (40 mL) and the mixture was refluxed for 20 h. The solvents were evaporated to dryness, residue boiled in MeOH and diluted with EtOAc. The resulting precipitate was filtered and washed with EtOAc and dried to give essentially pure 17 (5.0 g, 97%); mp (MeOH/EtOAc) 275-280° C.; 1H NMR [(CD3)2SO] δ 12.50 (br, 1 H, N+H), 10.75 (br s, 1 H, NH), 9.75 (br s, 2 H, NH2), 7.85 (br s, 4 H, NH2 & ArH)), 7.34 (d, J=8.6 Hz, 2 H, ArH), 6.24 (br s, 1 H, ArH), 2.79 (s, 3 H, CH3), HRMS (FAB+) calc. for C11H14N5 (M+1) m/z 216.1249, found 216.1247.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]2=[O:21])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]2=[O:21])=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(-n2ccc(C(=O)O)cc2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-n2ccc(C(=O)O)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 1-(4-Ethoxycarbonyl-phenyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (1.155 g) in THF (20 mL) at 0° C. was added 5 M sodium hydroxide (1.19 mL) and mixture stirred overnight at ambient temperature. Reaction mixture was acidified to pH 1 with concentrated HCl, producing a precipitate. The solid was collected by filtration, washed with H2O and dried under high vacuum to give 1-(4-Carboxy-phenyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (0.7196 g). LCMS-ESI−: calc'd for C13H8NO5: 258.2 (M−H+). Found: 258.1 (M−H+).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccnc(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
Under a dry nitrogen atmosphere a solution of 12.0 ml (0.096 mole) of phenyl chloroformate in 300 ml of methylene chloride was added dropwise to a cold (0° C.) stirred solution of 10.2 g (0.079 mole) of 4-amino-2-chloropyridine and 16.5 ml (0.12 mole) of triethylamine in 300 ml of methylene chloride. After complete addition the reaction mixture was allowed to come to room temperature and stirred at room temperature for approximately 18 hours. The mixture was washed with three 100 ml portions of water followed by 100 ml of an aqueous saturated sodium chloride solution. The washed mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was subjected to column chromatography on silica gel, eluted with acetone:methylene chloride (4:96), to yield 7.4 g of phenyl N-(2-chloro-4-pyridinyl)carbamate as a solid.