Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=1)[OH:11]>CS(C)=O.O.C1OCCOCCOCCOCCOCCOC1>[Cl:8][C:7]1[C:2]([O:11][C:10]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Oc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
2,3,5-Trichloropyridine (69.32 g, 0.38 mol) and 18-crown-6 (4.0 g, 0.015 mol) are added to a mixture of the dipotassium salt of hydroquinone (prepared from hydroquinone (44.0 g, 0.4 mol) and potassium hydroxide (45.0 g, 0.8 mol)) in dimethyl sulfoxide (700 mL). The reaction mixture is stirred overnight at room temperature, heated at 60° C. for 21/2 hours, diluted with water and extracted with ether. The combined organic extracts are washed with water, treated with charcoal, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title product as a white solid (47.23 g, mp 122°-123.5° C.)
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:14])[C@H:6]([OH:13])[C@H:7]([OH:12])[C@@H:8]([OH:11])[CH:9]=O)=[N+]=[N-].B(F)(F)F.[CH3:19]COCC.CCOC(C)=O.CCCCCC>C(O)C1C=CC=CC=1>[CH3:19][O:11][C@@H:8]1[C@H:7]([OH:12])[C@@H:6]([OH:13])[C@H:5]([OH:14])[CH2:4][NH:1][CH2:9]1
Reactant: CCOCC
Reactant: [N-]=[N+]=NC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: OCc1ccccc1
Product: CO[C@H]1CNC[C@@H](O)[C@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A suspension of 6-azido-6-deoxy-D-galactose 14 (1.63 g, 7.9 mmol) obtained as describe above in benzyl alcohol (5 mL) was heated to 80° C. and BF3.OEt2 (984 μL, 8 mmol) was added dropwise. After 20 minutes the suspension became transparent. The solution was allowed to cool down. The reaction mixture was passed through a SiO2 column. Benzyl alcohol came out first using EtOAc:Hexane 1:5, then benzyl 6-azido-6-deoxy-D-galactopyranoside was separated from the furanose byproduct with EtOAc as eluent (1.21 g, 75%, α/β 60:40): 1H-NMR (CD3OD, δ, ppm, α-anomer only): 7.4-7.6 (5H, Benzyl group); 5.3 (H1, overlapped by HDO signal); 4.98 and 4.78 (2H, AB system, J=12 Hz, CH2—OBn); 4.18 (1H, dd, J=4.2 Hz, 8.7 Hz, H5); 4.0 (3H, overlapped, H2, H3, H4); 3.75 (1H, dd, J=13 Hz, 8.7 Hz, H6); 3.49 (1H, dd, J=13 Hz, 4.2 Hz, H6′). 13C-NMR (CD3OD, δ, ppm, α-anomer only): 139.76, 131.64, 130.31, 100.28, 72.54, 72.36, 72.10, 71.36, 70.89, 53.62.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:48]1[NH:53][CH2:52][CH2:51][N:50]2[CH2:54][CH2:55][CH2:56][CH:49]12>CN(C=O)C>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:53]3[CH2:52][CH2:51][N:50]4[CH2:54][CH2:55][CH2:56][CH:49]4[CH2:48]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: C1CC2CNCCN2C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN4CCCC4C3)cn2)c1O
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (500 mg, 1.561 mmol), EDC (449 mg, 2.342 mmol) and HOBT (316 mg, 2.342 mmol) in DMF (3122 μl) and treated with DIPEA (818 μl, 4.68 mmol). Octahydropyrrolo[1,2-a]pyrazine (296 mg, 2.342 mmol) was then added. The reaction was allowed to stir for 8 hours and filtered and the filtrate was purified by preparative HPLC (15-40% ACN/water under basic conditions) to give a solid which was recrystallized from MeOH, filtered, and dried in vacuum to give the title compound (286 mg, 0.603 mmol, 38.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (br. s., 1H) 1.72 (br. s., 3H) 2.12 (br. s., 1H) 2.23 (d, J=7.07 Hz, 2H) 2.42 (s, 3H) 2.51-2.53 (m, 1H) 3.06 (t, J=8.08 Hz, 3H) 3.72 (br. s., 1H) 4.44-4.56 (m, 1H) 7.63 (dd, J=8.08, 1.77 Hz, 1H) 7.69 (d, J=1.26 Hz, 1H) 7.84 (d, J=8.08 Hz, 1H) 8.04 (dd, J=8.59, 2.27 Hz, 1H) 8.09 (s, 1H) 8.40 (d, J=7.58 Hz, 1H) 8.52 (d, J=2.27 Hz, 1H); ESI-MS m/z (M+H)+ calc'd for C24H24N6O2, 429.20. found 429.3.
Reaction SMILES: CC([O-])(C)C.[K+].CC(O)(C)C.[CH2:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)[C:13]#[CH:14]>O>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=[C:13]=[CH2:14]
Reactant: C#CCOc1ccc(C(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C=C=COc1ccc(C(=O)O)cc1
Yield: 43 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 7.920 parts of t-BuOK and 44.882 parts of t-BuOH and to this, a mixture of 10,000 parts of 1-propargyloxybenzene-4-carboxylic acid and 23.333 parts of t-BuOH was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. t-BuOH layer and water layer were removed by using an evaporator, and the residue was added with 1N-HCl and then extracted with an ether. The ether solvent was removed and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 1-allenyloxy benzene-4-carboxylic acid as a colorless clear oily product. This compound was identified by FT-NMR(H) and IR spectrum. The reaction yield was 43.0%.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:43]1([C:49]2[CH:50]=[CH:51][C:52]([NH2:55])=[N:53][CH:54]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:17])[CH2:13][C:14]([NH:55][C:52]2[CH:51]=[CH:50][C:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:54][N:53]=2)=[O:16])[CH2:10][CH2:11]1)=[O:5]
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 27.1 %

Procedure:
DMAP (137 mg, 1.1 mmol) was added to 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid (200 mg, 0.56 mmol) in DMF (2 mL) followed by EDCI (129 mg, 0.67 mmol) and HOBT (91 mg, 0.67 mmol). After 2 minutes, 5-phenyl-pyridin-2-ylamine (115 mg, 0.67 mmol) was added and stirring was continued at room temperature overnight. Cold water was then added and it was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 77 mg (27% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(5-phenyl-pyridin-2-yl)-propionamide. LC/MS [M+H]+: 507.1, 97.03%. 1H NMR (300 MHz, DMSO-d6): δ 10.8 (d, 1H), 8.7-8.6 (bs, 1H), 8.2-8.06 (m, 2H), 7.76-7.64 (m, 3H), 7.54-7.34 (m, 6H), 3.8-3.4 (m, 8H), 3.24-3.1 (m, 2H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:14]([O:13][C:7](=[O:12])[CH2:8][C:9]1([CH3:11])[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1)[CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1(C)OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 7.14 grams (0.055 moles) ethyl acetoacetate is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with 10% aqueous sodium bicarbonate to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 9.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 4 fractions:
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[S:16](Cl)(=[O:18])=[O:17].S(Cl)(Cl)(=O)=O.[OH-].[Na+].OS(O)(=O)=O>O.O1CCOCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[S:16]([OH:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=S(O)c1cc(F)c(F)cc1F
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of sodium sulfite (153 g, 1214 mmol) in 1000 mL water was added a solution of 2,4,5-trifluorobenzene-1-sulfonyl chloride (40 g, 173 mmol) in dioxane (300 mL) dropwise. After the complete addition of sulfonyl chloride, the reaction was basified to about pH 14 by the addition of 1 N NaOH, and the reaction mixture was stirred overnight. The reaction mixture was cooled in ice bath and acidified using ˜100 mL concentrated H2SO4 to pH about 1. The mixture was extracted with EtOAc and CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered and concentrated to afford 2,4,5-trifluorobenzenesulfinic acid (34 g, 100%).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]1([CH3:12])[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1>>[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: Cc1ccccc1C
Reactant: C=CC=C
Product: C=CCCCc1ccccc1C

Procedure:
The synthesis of 2,6-NDC typically includes several steps. In a typical synthesis, orthoxylene and butadiene are reacted over an alkali metal or other catalyst to yield a 5-orthotolylpentene (5-OTP) alkenylation product. The 5-OTP is then cyclized over an acid catalyst to yield 1,5 dimethyltetralin (1,5-DMT). The 1,5 DMT is dehydrogenated over a noble metal or some other dehydrogenation catalyst to yield 1,5-dimethylnaphthalene(1,5-DMN), which is subsequently isomerized to produce 2,6-dimethylnaphthalene (2,6-DMN).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](F)[N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[S:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([O:10][C:11]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[S:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)nc(Br)c1
Reactant: Oc1csc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)nc(Oc2csc(C(F)(F)F)c2)c1
Temperature: 80 °C
Yield: 65 %

Procedure:
A solution of 2-bromo-6-fluoro-4-methyipyridine (1.00 g, 5.26 mmol) and 4-hydroxy-2-(trifluoromethyl)-thiophene (0.88 g, 5.26 mmol) in dimethylformamide is treated with K2CO3 (1.09 g, 7.89 mmol), heated at 80° C. for 23 hours, cooled to room temperature, poured onto water, acidified to pH 5-6 with 6N HCl and extracted with ether. The ether extracts are combined, washed sequentially with water and brine, dried over MgSQ4 and concentrated in vacuo to give a residue. The residue is chromatographed (silica gel, ethyl acetate/hexanes, 3/97) to afford the title produce as a yellow oil, 1.16 g (65% yield), identified by 1HNMR and 19FNMR analyses.
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N+:12]([CH2:16][CH2:17][CH3:18])[CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].[BH3-]C#N.[Na+]>CO>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH:15]=2)=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20]
Reactant: CCC[n+]1cccc(-c2ccc(OC)c([N+](=O)[O-])c2)c1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCCN1CCC=C(c2ccc(OC)c([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a solution of 3-[4-(methyloxy)-3-nitrophenyl]-1-propylpyridinium iodide (6.10 g, 15.22 mmol) in methanol (100 mL) was added NaBH3CN (9.58 g, 152.06 mmol, Aldrich) and the reaction was allowed to stir overnight at rt. The reaction was quenched with water (50 mL), solvent removed under reduced pressure, aqueous layer extracted with dichloromethane (2×50 mL), organic layers combined, taken to a residue under reduced pressure, and purified by column chromatography on SiO2 to provide 5-[4-(methyloxy)-3-nitrophenyl]-1-propyl-1,2,3,6-tetrahydropyridine (1.89 g, 45% over two steps). ESIMS (M+H)+=277.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20]Br.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a solution of 1-(4-nitro-phenyl)-piperazine (2 g, 9.66 mmol) in DMF (10 mL) was added 3-bromopropionic acid methyl ester (1.6 g, 9.66 mmol) and the mixture was stirred at ambient temperature for 16 h. Water was added to the reaction, followed by adjusting pH to 7 with sat. aqueous NaHCO3. The resulting precipitate was collected by filtration and washed with water to furnish the title compound as a yellow solid (1.8 g, 63.6%): MS (ESI) m/z 294 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.55 (t, J=7.2 Hz, 2H), 2.62 (t, J=4.8 Hz, 4H), 2.77 (t, J=6.8 Hz, 2H), 3.42 (t, J=5.2 Hz, 4H), 3.71 (s, 3H), 6.81-6.83 (m, 2H), 8.11-8.14 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][NH:4][C:3]1=[O:7].[Cl:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH2:12][N:4]1[C:3](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:6][O:5]1
Reactant: CC1(C)CONC1=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CON(Cc2ccc(F)cc2Cl)C1=O
Yield: 107.5 %

Procedure:
By the method of Example 6, Step B, 95.6 g (0.83 mole) of 4,4-dimethyl-3-isoxazolidinone, 186 g (0.83 mole) of 2-chloro-4-fluorobenzyl bromide, 114.7 g (0.83 mole) of potassium carbonate, and 2.2 g (0.008 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane were reacted at room temperature in 1500 ml of acetonitrile, yielding 230 g of impure 2-[(2-chloro-4-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.O.CN([CH:22]=[O:23])C>>[OH:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:22]=[O:23]
Reactant: Oc1cc2ccccc2cc1O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c(O)c(O)cc2ccccc12
Reaction time: 4 h

Procedure:
Phosphorous oxychloride (1.9 ml) was added to a solution of 2,3-dihydroxynaphthalene (3.2 g) in DMF (26 ml) at 0° C. The reaction mixture was kept for four hours at 100° C. Water (50 ml) was added to the cooled mixture and the resulting oily suspension refluxed for 20 min. The cool reaction mixture was poured into ice, filtered, washed with water and recrystallized from 2-propanol-water. Yield: 0.1 g, melting point 129-134° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[N:19][N:20]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1)(=[O:3])[CH3:2].C1COCC1.CO.[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:25]([N:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([C:10]3[N:7]4[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]4=[N:12][CH:11]=3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A solution of 7-acetyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 146; 10 mg, 0.024 mmol) in a 1:1 THF/MeOH mixture (0.2 mL) was treated at ambient temperature with excess sodium borohydride (3.7 mL, 0.10 mmol), and stirring continued overnight. The reaction was quenched with excess saturated aqueous sodium bicarbonate and the resulting suspension was extracted with EtOAc and DCM. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with MeOH/DCM as eluent to afford 8.8 mg of the desired product as a white solid. MS (ES+APCI) m/z=412 (M+H) detected.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:15](=O)[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1)C1C=CC=CC=1.[O-]S([O-])(=O)=O.[Na+].[Na+].O>C1COCC1>[CH3:15][NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](O)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of 37.9 g (0.94 mol, 2.0 eq) LAH in 1.3 l THF was added a suspension of 117 g (0.47 mol) trans-4-Hydroxy-cyclohexylcarbamic acid benzyl ester in 1 l THF over a period of 6 h via a cannula keeping the temperature between 5–10° C. The reaction was refluxed over night and a mixture of Na2SO4, silica gel and water (160 g, 50 g, 80 ml) was added, stirred for additional 30 min, filtered and concentrated. The crude material was titurated with hexane to yield 27.9 g (46%) trans-4-Methylamino-cyclohexanol. Column chromatography of the mother liquor on silica gel yielded additional 17.1 g (28%) trans-4-Methylamino-cyclohexanol as white solid, MS: 129 (MH+) (in analogy to Venuti, Michael C.; Jones, Gordon H.; Alvarez, Robert; Bruno, John J.; J. Med. Chem.; 30; 2; 1987; 303–318).
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[C:17]([CH2:20][OH:21])[S:18][CH:19]=1>>[OH:21][CH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][S:13][CH2:12][CH2:11][NH:10][C:3]([NH:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])[N:16]=1
Reactant: NCCSCc1csc(CO)n1
Reactant: CNC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCc1csc(CO)n1

Procedure:
The process of claim 1 wherein the N-[2-[[[2-(hydroxymethyl)-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine is prepared by reaction of 2-methylamino-2-methylthio-1-nitroethylene with 4-[[(2-aminoethyl)thio]methyl]-2-hydroxymethyl thiazole.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([NH2:12])[C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>CO.[Pt]=O>[NH2:12][C:6]1[C:7]([NH2:11])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][NH:1]2
Reactant: Nc1ccc2ncccc2c1N
Agent: O=[Pt]
Agent: O=S(=O)(O)O
Solvent: CO
Product: Nc1ccc2c(c1N)CCCN2
Reaction time: 44 h

Procedure:
A solution of 5,6-quinolinediamine (12.5 g, 0.065 mol) and sulfuric acid (8 mL) in methanol (250 mL) was treated with platinum oxide (1 g) in a Parr apparatus under hydrogen for 16 hours. An additional 1 g portion of platinum oxide was added and hydrogenation continued for 44 hours additional. Standard work-up gave the 5,6-diaminotetrahydroquinoline.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].CCN(C(C)C)C(C)C.C(OC([O-])=O)(ON1C(=O)CC([C:24]([O:26][CH2:27][CH:28]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])C1=O)=O.O>CN(C=O)C>[C:24]([NH:5][CH2:4][C:3]#[N:2])([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:25]
Reactant: N#CCN
Reactant: O=C([O-])OC(=O)ON1C(=O)CC(C(=O)OCC2c3ccccc3-c3ccccc32)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Aminoacetonitrile HCL salt (1 mmol (92.53 mg)) is dissolved in DMF 2 ml and DIEA 2 mmol 0.35 ml. Then Fmoc-Succinimidyl dicarbonate 1.1 mmol, (350 mg) is added and the reaction allowed to proceed overnight. Water and diluted HCL is added to bring the pH to 2. The product is extracted 3 times with ethylacetate and dried over Na2SO4 to yield Fmoc-NH—CH2—CN. 1 mmol of the Fmoc-NH—CH2—CN (278 mg) is dissolved in 2 ml of anhydrous methanol bubbled with HCl gas. The reaction is kept at 0° C. for 40 hrs (Voss and Gerlach Helv. Chim. Acta (1983) 66: 2294) to yield the desired Fmoc-glycine orthotrimethylester (Fmoc-NH—CH2—C(OCH3)3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1>C(O)C>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCc1ccc(CCl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a solution of indole (4.0 g, 34.1 mmol), potassium hydroxide (2.40 g, 42.6 mmol) in ethanol (200 mL) was added and the mixture solution was stirred at room temperature for two hours. The solvent was distilled under reduced pressure. The residue was dissolved in acetone (200 mL), and 1-chloromethyl-4-ethylbenzene (5.28 g, 34.1 mmol) was added thereto. The reaction mixture was stirred at room temperature a whole day and night, and then subjected to Celite filtration and the filtrate was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:500)] to obtain the title compound (3.8 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][CH2:21][F:22])[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:26][CH3:25])[C:12]=2[O:19][CH2:20][CH2:21][F:22])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCF
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1OCCF
Yield: 43 %

Procedure:
4-Chloro-2-[2-(2-fluoroethoxy)-3-formylphenoxy]benzonitrile (0.35 g, 1.1 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 16 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration and dried to give 4-chloro-2-[2-(2-fluoroethoxy)-3-(methylaminomethyl)phenoxy]benzonitrile fumarate (194 mg, 40%) as a beige solid.