Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:24].CCN(C(C)C)C(C)C.[Cl:34][C:35]1[CH:40]=[N:39][C:38](Cl)=[CH:37][N:36]=1.C(OCC)C>CN(C=O)C>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:21]2[CH2:22][CH2:23][CH:18]([N:15]3[CH2:16][CH2:17][C@H:13]([NH:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:14]3=[O:24])[CH2:19][CH2:20]2)=[N:39][CH:40]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)c(F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
To a solution of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 3 g, 8.44 mmol) and DIEA (7.35 mL, 42.2 mmol) in DMF (30 mL) was added 2,5-dichloropyrazine (2.51 g, 16.9 mmol). This mixture was degassed with nitrogen for 30 minutes then stirred at 100° C. for 4 hours under nitrogen. The mixture was poured into brine (500 mL) and extracted into ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil. Diethyl ether (200 mL) was added and a precipitate formed overnight. The ether was decanted and the solid was triturated using ethanol (100 mL) at reflux with stirring for 5 minutes. The suspension was filtered and the solid was washed using ethanol to give a solid crystal. This solid was dried over the weekend under high vacuum to provide the title compound (2.9 g, 73% yield). Mass spectrum (apci) m/z=468.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][N:10]2[C:22]([O:24][CH:25]2[CH2:30][CH2:29][N:28](C(OCC3C=CC=CC=3)=O)[CH2:27][CH2:26]2)=[O:23])[CH:2]=1.C([O-])=O.[NH4+]>CCO.[OH-].[OH-].[Pd+2]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:12][CH2:11][N:10]2[C:22]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:23])[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC2CCN(C(=O)OCc3ccccc3)CC2)C(COc2cccnc2)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC2CCNCC2)C(COc2cccnc2)C1
Temperature: 70 °C

Procedure:
Palladium hydroxide on carbon (˜10% Pd, 84 mg, 0.06 mmol) was added to a mixture of 1-(1-(benzyloxycarbonyl)piperidin-4-yl) 4-tert-butyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (0.665 g, 1.20 mmol) and ammonium formate (0.151 g, 2.40 mmol) in EtOH (10 mL). The reaction mixture was heated to 70° C. for 2 h. Upon cooling to rt, the reaction mixture was filtered though Celite®, and the filtrate was concentrated under reduced pressure. This gave 0.5278 g of crude product. LC-MS: RT=4.50 min, [M+H]+=421.2.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCc3ccccc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and benzyl amine to afford the title compound. MS: m/e=348 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].ClC(Cl)(Cl)C.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:7][O:6][Si:5]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:3][CH2:2][NH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: NCCN1CCNCC1
Solvent: CC(Cl)(Cl)Cl
Product: CO[Si](CCCNCCN1CCNCC1)(OC)OC
Temperature: 80 °C
Yield: 93.7 %

Procedure:
A one-liter, four-necked flask was equipped with a thermometer, a condensor, an inlet tube for nitrogen gas and an outlet tube for vent gases. Chloropropyltrimethoxysilane (198.72 g) was introduced into the flask, together with 50 g of anhydrrous 1,1,1-trichloroethane and 86.14 g of 1-(2-aminoethyl)- piperazine. The mixture was heated to 80° C. with continuous agitation for four hours and then cooled to room temperature. The reaction mixture was rapidly filtered to collect the 1-(2-aminoethyl)piperazine hydrochloride salt which had formed. The filtrate was distilled to yield 182 g of 1-[2-[3-(trimethoxysilyl)- propyl]aminoethyl]piperazine, bp 120°-143° C. at 10 mm Hg (69 kPa) as a pale yellow oil. The yield corresponded to 64% of theoretical. This material was used as an accelerator and adhesion promoter in the sealant compositions of this invention as detailed below in Example 5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1([F:19])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH:17]=O)=[CH:16][C:10]=2[O:9]1>[OH-].[OH-].[Pd+2].CO>[F:19][C:8]1([F:7])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH2:17][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:16][C:10]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 2 L Erlenmeyer flask was charged with piperazine (185.1 g, 2.15 mol), 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde (100.0 g, 0.537 mol), and methanol (1.08 L). The solution was stirred at room temperature for 18 h then passed twice through an H-Cube Midi™ (ThalesNano, Budapest, Hungary) with a new 20% Pd(OH)2/C MidiCart cartridge, at the following settings: 70° C., 1 atm pressure, 6 mL/min flow rate, and 10% excess H2 production. The aldehyde starting material was >90% consumed after the first pass, and completely consumed after the second pass as indicated by HPLC analysis. The methanol was evaporated, toluene (1.20 L) was added and the mixture was stirred at room temperature for 18 h. The resulting white suspension was filtered and the solid was rinsed with toluene (200 mL). The combined filtrate was washed with water (2×300 mL), dried over Na2SO4, filtered, and concentrated to afford the product as a colorless oil. The oil was dissolved in heptane (100 mL) and the product was allowed to crystallize at room temperature. For subsequent synthesis experiments, addition of a small amount of seed crystals was used to quicken the crystallization process. The suspension was cooled to 0° C., filtered and the solid was dried in vacuum oven at 50° C. for 24 h to give the title compound as a white solid (108.0 g, 78%). The heptane filtrate was concentrated to approximately 20 mL followed by addition of product seed crystals. The solution then was stirred overnight. The second batch of the title compound was obtained as a white solid after filtration and drying (6.7 g, 5%). The combined yield was (115 g, 83%). MS (ESI+): calcd for C12H14F2N2O2 m/z 256.1. found 256.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.11 (d, J=0.9 Hz, 1H), 6.99 (dd, J=9.0, 0.9 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 3.45 (s, 2H), 2.92-2.83 (m, 4H), 2.39 (s, 4H); 13C NMR (101 MHz, CDCl3) δ: 143.89, 142.72, 134.68, 131.65 (t, JC-F=255.3), 123.88, 110.13, 108.82, 63.10, 54.38, 46.07.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[Cl:34].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)COP([O-])(O)=O)C2=CC=1C.[Na+]>ClCCl.C(N(CC)CC)C.CCOC(C)=O>[Cl:34][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(Cl)c1)C2
Reactant: CCCC(=O)Cl
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O)c2cc1C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1Cl
Reaction time: 20 h
Yield: 58 %

Procedure:
Butyryl chloride (46 mg, 0.4 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (161 mg, 0.4 mmol) in dichloromethane (10 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 20 h, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white solid identified as the title compound (110 mg, 58%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=O)=[O:8].CN(C)C1C=CC=CC=1>P(Cl)(Cl)(Cl)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[N:12]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]cnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a stirring suspension of benzoyleneurea 1 (10.0 g, 61.7 mmol) and phosphorus oxychloride (20 ml) in a 500 mL three-necked round-bottomed flask equipped with a magnetic stirrer and reflux condenser, was added N,N-dimethylaniline (7.80 ml, 61.7 mmol) in a single portion. The suspension was heated at reflux for 3 hours and slowly formed a light red solution. The solution was concentrated under reduced pressure and the residue was poured onto ice (100 g). The solution was basified to pH=9.0 using concentrated aqueous sodium bicarbonate solution. The mixture was partitioned between CH2Cl2 and H2O. The organic portion was dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was dissolved in anhydrous THF (75 ml) and cooled to 0° C. Dimethylaniline (67.7 mL, 135 mmol, 2.0 M in THF) was added dropwise, with stirring, over a period of 30 minutes. The solution was then stirred at 0° C. for 1 hour. The solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography using (70% hexanes, 30% ethyl acetate) to obtain 2 (7.90 g, 38.1 mmol, 62% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([O-:14])=O)[N:8]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=2)[O:11][N:10]=1)=[O:14]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C([O-])c1noc(Cc2cccc(C(F)(F)F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cccc(C(F)(F)F)c2)n1
Yield: 37.7 %

Procedure:
This compound was prepared according to method F with 5-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate (0.039 g; 0.130 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.030 g; 0.130 mmol), HATU (0.050 g; 0.130 mmol), N,N diisopropylethylamine (0.056 mL; 0.324 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) an by preparative HPLC method 2 to yield 0.022 g (38%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2/[CH:13]=[C:14]1/[C:15](=[O:20])[NH:16][C:17](=[S:19])[S:18]/1.[CH3:21]CN(C(C)C)C(C)C.IC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2/[CH:13]=[C:14]1/[C:15](=[O:20])[N:16]=[C:17]([S:19][CH3:21])[S:18]/1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2[nH]c(C)c(/C=C3\SC(=S)NC3=O)c2c1
Solvent: CO
Solvent: CI
Product: COc1ccc2[nH]c(C)c(/C=C3\SC(SC)=NC3=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a room temperature suspension of (Z)-5-[(5 -methoxy- 2-methyl-1H -indol -3-yl)methylene]-2-thioxo-4-thiazolidinone (1.714 g, 5.63 mmols) in 50 mL of methanol is added Hunig's base (1.15 mL, 6.61 mmols) followed by iodomethane (0.500 mL, 8.03 mmols). The thick suspension is stirred overnight at room temperature. Filtration washing with ether provides 1.631 g (91%) of (Z)-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-2-(methylthio)-4-(5H)-thiazolone; mp 214°-222° C. dec. Calc'd for C15H14N2O2O2S2 :
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:24][NH2:25]>C(Cl)(Cl)Cl.C1COCC1.CCOCC>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([NH:24][NH2:25])=[O:14])=[CH:11][C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Temperature: -78 °C

Procedure:
4-Benzyloxy-3,5-dimethyl-benzoic acid (5.37 g, 20.9 mmol) is dissolved in CHCl3 (75 mL) and thionylchloride (10 mL) is added at rt. The mixture is stirred at reflux for 2 h. The mixture is evaporated to provide the crude acid chloride (5.62 g). A part of this material (2.75 g, 10 mmol) is dissolved in THF (10 mL) and cooled to −78° C. before it is treated with hydrazine (25 mL, 1 M solution in THF). The mixture is warmed to rt over a period of 15 h. The mixture is diluted with ether (150 mL) and washed with 1M aq. HCl (75 mL, then 5×50 mL). The combined aq. extracts are washed with ether (50 mL), basified with 33% aq. KOH and extracted with DCM (5×50 mL). The DCM extracts are dried over Na2SO4, filtered and evaporated to give 4-benzyloxy-3,5-dimethyl-benzoic acid hydrazide (1.29 g) as a white solid, LC-MS: tR=0.78 min, [M+1]+=271.19; 1H NMR (CDCl3): δ 2.30 (s, 6 H), 3.86 (s br, 2H), 4.82 (s, 2 H), 7.33-7.49 (m, 7 H), 7.56 (s br, 1 H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(O[C:15]([S-:17])=[S:16])C.[K+]>CN1CCCC1=O>[SH:17][C:15]1[S:16][C:2]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=2[N:4]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2sc(S)nc2c1
Temperature: 140 °C
Yield: 86.2 %

Procedure:
2-Bromo-5-nitroaniline (10 g) was dissolved in N-methyl-2-pyrrolidone (50 mL), and potassium ethylxanthate (14.8 g) was added thereto. The mixture was stirred at 140° C. with heating. The reaction mixture was concentrated under reduced pressure, and water (300 mL) and conc. hydrochloric acid (10 mL) were added to the residue. The precipitated solid was collected by filtration, which was then dissolved in 1 mol/L aqueous sodium hydroxide solution (80 mL). After washing with chloroform, 1 mol/L hydrochloric acid was added thereto, and the precipitated solid was collected by filtration to give 2-mercapto-5-nitrobenzothiazole (8.43 g) as an orange powder.
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[S:11])=[O:7])(=O)C.N>>[SH:4][CH2:5][C:6]([N:8]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[S:11])=[O:7]
Reactant: CC(=O)SCC(=O)N1C[C@@H](C)C[C@H]1C(O)=S
Agent: N
Product: C[C@H]1C[C@@H](C(O)=S)N(C(=O)CS)C1

Procedure:
Hydrolysis of (cis)-1-(2-acetylthio-1-oxoethyl)-4-methylthio-L-proline with an aqueous ammonia solution according to the procedure of Example 2 yields 1-(2-mercapto-1-oxoethyl)-cis-4-methylthio-L-proline.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:16]3[C:17](=[O:20])[CH2:18][CH2:19][C:15]=3[N:14]=[C:13]2[CH:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:16]3[CH:17]([OH:20])[CH2:18][CH2:19][C:15]=3[N:14]=[C:13]2[CH:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CC2
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
Sodium borohydride (155 mg) was added to a stirred solution of Intermediate 21 (660 mg) in dichloromethane (2 mL) and methanol (2 mL). The reaction mixture was stirred for 2.5 hours. More sodium borohydride (155 mg) was added. The RM was left stirring at room temp. under nitrogen for 1 hour. The reaction mixture was partitioned between EtOAc (50 ml) and water (30 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated; the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the title compound (660 mg). LC/MS MH+ 325, 327, Rt 1.63 min (5 minute run).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11]O)=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:32])=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][Cl:32])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(Cl)c(CCl)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
A solution of 1 g of 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-methoxycarbonyl-1,1'-biphenyl-4yl)methyl]-1H-imidazole in 20 ml of CHCl3 is added with 1.44 g of thionyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:18][CH:19]([O:25][CH:26]([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]=1[OH:8].IC.[C:31](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:18][CH:19]([O:25][CH:26]([CH3:27])[CH3:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:7]=1[O:8][CH3:31]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(Cc1cc(Br)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cc(Br)c(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
944 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was dissolved in 5 ml N,N-dimethylformamide, and 0.15 ml iodomethane and 500 mg of potassium carbonate were successively added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (4:1), 876 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropionate was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[O:11]>[Pd]>[CH:10]([CH:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])=[O:11]
Reactant: CC1=C(C=O)C(C)(C)CCC1
Agent: [Pd]
Product: CC1CCCC(C)(C)C1C=O

Procedure:
reducing β-cyclocitral through hydrogenation with a supported palladium catalyst in alcohol at about ambient temperature and at about atmospheric pressure to form 1-formyl-2,6,6-trimethylcyclohexane,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][CH2:38][C:39]2[NH:48][C:42]3=[N:43][CH:44]=[C:45](I)[CH:46]=[C:41]3[N:40]=2)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][CH2:38][C:39]2[NH:48][C:42]3=[N:43][CH:44]=[C:45]([C:2]4[CH:3]=[CH:4][C:5]([S:8]([N:11]5[CH2:12][CH2:13][N:14]([C:17]6[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=6)[CH2:15][CH2:16]5)(=[O:10])=[O:9])=[CH:6][CH:7]=4)[CH:46]=[C:41]3[N:40]=2)[CH:32]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: Cc1ccc(N2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(c6ccc(C)cc6)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 37.5 %

Procedure:
A mixture of 0.395 g of 1-(4-bromo-benzene-sulfonyl)-4-(p-tolyl)-piperazine, 0.28 g of bis-(pinacolato)-diboron, 0.017 g of 1,1′-bis-diphenylphosphino)-ferrocene, 0.022 g of [1,1′-bis(diphenylphosphine)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.294 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2for 16 hours. To the resulting mixture 4 ml of degassed dioxane, 0.228 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5b]pyridine (starting material A1), 0.069 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.165 g of potassium carbonate and 0.051 g of lithium chloride in 4 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 7.5 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with ethylacetate. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-20:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate/diethylether gives 0.128 g of the title compound as a brownish solid of m.p. 150-154° C. The mass spectrum shows the molecular peak MH+ at 569.5 Da.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C:19](=O)[CH2:18][O:17][C@@H:16]2[CH2:21][CH2:22][C:23]([F:25])([F:24])[C@@H:15]12)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][C@@H:16]2[CH2:21][CH2:22][C:23]([F:25])([F:24])[C@@H:15]12)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CO[C@@H]2CCC(F)(F)[C@H]2N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: FC1(F)CC[C@H]2OCCN(Cc3ccccc3)[C@@H]21
Temperature: 70 °C

Procedure:
LiAlH4 (176 mg, 4.63 mmol) was added to a solution of trans-4-benzyl-5,5-difluorohexahydrocyclopenta[b][1,4]oxazin-3(2H)-one (550 mg, 2.05 mmol) in THF (15 mL) at 0° C. The reaction mixture was heated at 70° C. for 2 hours and then cooled to room temperature. 5 mL of water was added slowly to quench the reaction and then the reaction was extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification of the residue on a silica gel column (0 to 40% EtOAc/hexanes) afforded trans-4-benzyl-5,5-difluorooctahydrocyclopenta[b][1,4]oxazine. MS ESI calc'd. for C14H17F2NO [M+H]+ 254. found 254.