Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[C:5]([SH:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[C:21]=1Cl.O>CN(C=O)C>[CH3:24][N:19]1[C:20](=[O:23])[C:21]2[S:9][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[S:8][C:17]=2[C:18]1=[O:25]
Reactant: CN1C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc(S)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2sc3c(=O)n(C)c(=O)c=3sc2c1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A stirred solution of 4-methylbenzene-1,2-dithiol (0.5 g) in anhydrous DMF (50 ml) was treated with K2CO3 and 3,4-dichloro-1-methyl-pyrrole-2,5-dione (0.73 g) and stirred for about 7 hours at 80° C. The reaction mixture was poured into water and extracted with MTBE. The combined organic phases were washed once with water and after removal of the solvent under reduced pressure the crude product (0.85 g) was purified by flash column chromatography on silica gel (cyclohexane/ethyl acetate 9:1) to yield the compound ex. I-2 (0.25 g); m.p.: 171-176° C.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A large excess of Raney® nickel was added in portions to a stirred solution of ethyl 1-(4-nitrobenzyl)-1H-indole-2-carboxylate (0.65 g, 2 mmol), hydrazine (0.5 mL, 16 mmol) in 25 mL of ethanol. After stirring at room temperature for 2 hours the catalyst was then removed by filtering through a short pad of Celite®521. The filtrate was concentrated to give ethyl 1-(4-aminobenzyl)-1H-indole-2-carboxylate (MS (ESI) m/z 294.2 (MH+) as a gummy solid. The gummy solid was then dissolved in 15 mL of methylene chloride. To the solution was added diisopropylethylamine (0.5 mL, 2.9 mmol) and biphenyl 4-sulfonyl chloride (0.5 g, 1.0 mmol). After being stirred at room temperature overnight the reaction was concentracted and the residue was re-dissolved in 15 mL of 2:1:1 THF/MeOH/water. Lithium hydroxide monohydrate (0.2 g, 4.8 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by semi-preparative HPLC. The product was collected based on UV absorption and concentrated to give the title compound as a brown solid (0.11 g, 22%): 1H NMR (DMSO-d6) δ 5.75 (s, 2H), 6.93 (d, J=8.9 Hz, 2H), 7.01 (d, J=8.9 Hz, 2H), 7.09 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.40-7.55 (m, 4H); 7.65-7.80 (m, 3H), 7.75-7.82 (m, 4H), 10.30 (s, 1H), 12.93 (s, 1H); HRMS calcd for C28H23N2O4S: 483.1367; found (ESI+): 483.1374; Anal. calcd for C28H22N2O4S .0.2H2O: C, 69.18; H, 4.64; N, 5.76. Found: C, 69.21; H, 4.60; N, 5.78.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CN(C)C=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.C(OCC)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:25][CH:24]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: OC(c1ccccn1)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
The 2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (88 mg, 0.40 mmol) obtained in Referential Example 3 was dissolved in thionyl chloride (2.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide, followed by stirring for 15 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and the resulting mixture was concentrated further. The residue was dissolved in dimethylformamide (5 ml). To the resulting solution were added 4-chlorobenzenethiol (79 mg, 0.55 mmol) and potassium carbonate (226 mg, 1.64 mmol) under a nitrogen atmosphere, and the mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (128 mg, 92%) as an oil.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:22]=C=NC(C)C)(C)C.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([NH2:22])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)nc1
Reactant: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.415 mmol) of 3-(6-phenoxy-pyridin-3-yl)-acrylic acid was dissolved in 4 ml of DMF, and 52 mg (0.415 mmol) of N,N′-diisopropylcarbodiimide and 126 mg (0.830 mmol) of the ammonium salt of benzotriazol-1-ol were added. After 1 h a further 126 mg (0.830 mmol) of the ammonium salt of benzotriazol-1-ol were added. The reaction was stirred at room temperature for 16 h, filtered, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 75 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH2:21]([CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=O)[CH2:24]1)[CH3:22].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]([CH2:21][CH3:22])[CH2:24]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CCC1CC(=O)c2ccccc21
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CCC1CC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c2ccccc21

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-3-ethyl-indan-1-one (prepared according to Kousik K., J. Am. Chem. Soc. 2005, 127, 16042) using decaborane yielded a mixture of isomers of the title compound as a white solid. MS (ESI): m/z=423.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:24]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccccc1F)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
A sample of 19.53 g of 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane, 10.59 g of sodium carbonate and 15.8 g of o-fluorobenzoyl chloride are reacted to give the prodct 3-(o-fluorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as a brown gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([C:20](OCC)=[O:21])=[CH:19][C:12]=2[N:11]=1.C[Al](C)C.[CH3:30][C:31]1[C:36]([CH3:37])=[CH:35][N:34]=[C:33]([NH2:38])[CH:32]=1>CCCCCC.C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([C:20]([NH:38][C:33]3[CH:32]=[C:31]([CH3:30])[C:36]([CH3:37])=[CH:35][N:34]=3)=[O:21])=[CH:19][C:12]=2[N:11]=1
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)n(C)c2cc1F
Reactant: Cc1cnc(N)cc1C
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc3nc(Nc4c(Cl)cccc4Cl)n(C)c3cc2F)cc1C

Procedure:
Prepared analogously to example 131f from ethyl 2-(2,6-dichlorophenylamino)-6-fluoro-1-methyl-1H-benzimidazole-5-carboxylate, 2 M trimethyl aluminium solution in hexane and 4,5-dimethylpyridin-2-amine in THF.
Reaction SMILES: [C:1](OC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[CH2:1]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCC(O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Product: CCCCCCCC/C=C\CCCCCCCCNCC(O)CO
Reaction time: 24 h

Procedure:
5 g of methyl oleat (commercially available under the trade name EDENOR®ME V05 from Cognis GmbH, MW 296) and 1.54 g of 3-amino-1,2-propanediol (MW 91.1, Sigma-Aldrich) were mixed together at 70° C. After addition of 100 mg of Novozym®435 (lipase B from Candida Antarctica, from Novozymes), the reaction was conducted during 24 h at 70° C. under moderate agitation and vacuum (250-300 mbars). The mixture was filtrated to remove the immobilized enzyme. The product of the reaction was analyzed by HPLC-DEDL, to give an area ratio of N-oleyl-(3 amino-1,2-propanediol)/substrates>83%. Thus N-oleyl-(3 amino-1,2-propanediol) is a substance according to formula (I), wherein R1=—(CH2)7—CH═CH—(CH2)7—CH3 and R2=CH2—OH
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=2[F:29])[N:17]=1.[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:31]#[C:30][CH:32]3[CH2:34][CH2:33]3)=[CH:24][C:23]=2[F:29])[N:17]=1
Reactant: C#CC1CC1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(I)cc3F)c(=O)[nH]2)c1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1)C(F)(F)F
Yield: 43.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(1-(2-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Intermediate-126, 1.100 g, 3.88 mmol), ethynylcyclopropane (0.127 g, 1.93 mmol), TBAF (1.10 g, 3.88 mmol), bis(triphenylphosphine)palladium(II) chloride (0.036 g, 0.051 mmol) and DMSO (3.0 mL) to afford 0.400 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 0.95 (m, 4H), 1.56 (m, 1H), 4.44 (br s, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.42-7.46 (m, 2H), 7.58 (t, J=7.8 Hz, 1H), 7.65 (m, 3H), 10.12 (br s, 1H); MS (m/z): 479.11 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23](B4OC(C)(C)C(C)(C)O4)=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH:35]([CH3:37])[CH3:36])[CH3:14])=[CH:8][C:7]=1[CH3:38].CC(O)=[O:42].OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([OH:42])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH:35]([CH3:37])[CH3:36])[CH3:14])=[CH:8][C:7]=1[CH3:38]
Reactant: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2C(C)C)cc1C
Reactant: CC(=O)O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(O)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of 3-[4-(1-{4-Isopropyl-2-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-ethoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.88 g, 1.69 mmol) in THF (5 ml) at 0° C. is treated with HOAc (150 mg, 2.54 mmol), followed by addition of mixture of H2O2 (4.0 ml, 30%) in H2O (0.8 ml). The reaction mixture is stirred for 2 hours while warmed to room temperature. The mixture is then cooled back to 0° C. and treated with saturated aqueous Na2S2O3 (30 ml) carefully. The mixture is then extracted with EtOAc (3×100 mL) and the combined organics are dried over Na2SO4 and concentrated, purified by silica gel chromatography (Hexanes/EtOAc, 7/3 to 5/5) to afford the phenol as a colorless oil (0.62 g, 87%). MS (MH+): 424.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=3[NH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=3[NH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: Nc1nccc2[nH]cc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccc(-c2c[nH]c3ccnc(N)c23)cc1
Yield: 92.9 %

Procedure:
Platinum oxide (catalytic) was added to a solution of 3-(4-nitrophenyl)-1H-pyrrolo[3,2-c]pyridin4-amine (0.006 g, 0.024 mmol, 1.0 eq) in MeOH (1 mL) and the reaction mixture was stirred at room temperature under a blanket of hydrogen (50 psi) for 1 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the product (0.005 g, 100%) as a solid. MS(ESI+) m/z 225 (M+H)+. Calculated: 225.1140, found: 225.1141.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:14](=[O:15])[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[N:6]2[C:20]=1[CH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)=O.[Cl-].[OH:28][NH3+:29].C([O-])(=O)C.[Na+].O>CO>[OH:28][N:29]=[CH:1][C:3]1[N:4]=[C:5]2[C:14](=[O:15])[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[N:6]2[C:20]=1[CH2:21][C:22]1[NH:26][CH:25]=[CH:24][N:23]=1
Reactant: [NH3+]O
Reactant: O=Cc1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n2c(Cc3ncc[nH]3)c(C=NO)nc12
Temperature: 70 °C
Yield: 57.8 %

Procedure:
To a solution of 2-formyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (250 mg, 0.69 mmol) in methanol (10 ml) was added a mixture of hydroxylammonium chloride (65 mg, 0.95 mmol) and sodiumacetate (150 mg, 1.10 mmol) in methanol (10 ml). The reaction mixture was heated at 70° C. for 1.5 h, followed by addition of water (10 ml). The precipitate was filtered off and washed with water. Recrystalization from isopropanol/petroleum ether gave 150 mg (58%) of the title compound. M.p. 227.5°-228° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.FC(F)(F)C([O-])=[O:22]>>[OH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:6]2[N:7]=[C:2]([OH:22])[CH:3]=[CH:4][C:5]=2[N+:16]([O-:18])=[O:17])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1N[C@H]1CC[C@H](O)CC1
Reactant: O=C([O-])C(F)(F)F
Product: O=[N+]([O-])c1ccc(O)nc1N[C@H]1CC[C@H](O)CC1

Procedure:
From trans-4-(6-chloro-3-nitropyridin-2-ylamino)cyclohexanol, trifluoroacetate, prepared in a similar manner as the one described in Example 1.3, Step B, the title compound was obtained. LCMS m/z=254.4 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][OH:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH:15]=[O:16]
Reactant: OCc1cccc2cc(-c3nccs3)[nH]c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=Cc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of [2-(1,3-thiazol-2-yl)-1H-indol-7-yl]methanol (0.610 g) in dichloromethane (50 mL) was added Dess-Martin oxidant (1.50 g), and the mixture was stirred at room temperature for 0.5 hr. the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution and 1N aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-50:50) to give the title compound (0.450 g, yield 74%) as pale-yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:10]2([CH2:15][CH2:14][NH:13][CH:12]([C:16]([NH:18][C:19]3([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)=[O:17])[CH2:11]2)[CH2:9]1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:32][C:33]([F:42])([F:43])[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][N:13]1[CH2:14][CH2:15][C:10]2([CH2:9][CH2:8]2)[CH2:11][CH:12]1[C:16]([NH:18][C:19]1([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)=[O:17]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3)CC4)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3cccc(C(F)(F)F)c3)CC4)CC2)cc1
Yield: 113.4 %

Procedure:
The title compound (D125) (60.7 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-(6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate 2,2,2-trifluoroacetate (single unknown enantiomer) (D90) (50 mg, 0.11 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.020 ml, 0.12 mmol). (Cs2CO3:2 eq; reaction time: 4 hrs; reaction temperature: RT.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.O.[Fe]>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]=[C:11]([Cl:19])[C:10]=1[NH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 100764.1 %

Procedure:
Benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridine-4-yl)-amine (345 mg, 1.0 mmol) was dissolved in a mixture of AcOH (18 ml) and water (2 ml). Fe powder (349 mg, 6.2 mmol) was added and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (10 ml) and water (10 ml). The mixture was filtered through celite, washing through with EtOAc (20 ml). The layers were separated and the organic layer was washed with sat. NaHCO3 (aq) (2×10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound (304 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:45]1([N:49]2[CH2:55][CH2:54][CH2:53][N:52]([C:56]([N:58]3[CH2:61][CH:60]([NH2:62])[CH2:59]3)=[O:57])[CH2:51][CH2:50]2)[CH2:48][CH2:47][CH2:46]1>CN(C=O)C.C(Cl)Cl>[CH:45]1([N:49]2[CH2:55][CH2:54][CH2:53][N:52]([C:56]([N:58]3[CH2:59][CH:60]([NH:62][C:6]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:10][CH:9]=4)=[O:8])[CH2:61]3)=[O:57])[CH2:51][CH2:50]2)[CH2:48][CH2:47][CH2:46]1
Reactant: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a stirred solution of 6-methylnicotinic acid (5.5 mg, 40 μmol) in 1:1 DCM:DMF (1 ml) was added HOBt (12 mg, 87 μmol) followed by HBTU (30 mg, 80 μmol) at room temperature. After 15 minutes 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine (10 mg, 40 μmol) was added and the reaction was stirred for 16 hours. The reaction was concentrated at reduced pressure and purified directly via preparative HPLC to give the title compound (5 mg, 34%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[N:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([O-])=O.[CH:18](OC)(OC)OC.FC(F)(F)C(O)=O>[Ni].CO>[O:14]1[CH2:15][CH2:16][CH:11]([N:10]2[C:9]3=[N:8][C:7]([OH:17])=[CH:6][CH:5]=[C:4]3[N:1]=[CH:18]2)[CH2:12][CH2:13]1
Reactant: COC(OC)OC
Reactant: O=[N+]([O-])c1ccc(O)nc1NC1CCOCC1
Agent: [Ni]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Oc1ccc2ncn(C3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
5-Nitro-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-ol (0.173 g, 0.723 mmol) and methanol (160 mL) were stirred at 25° C. for 4 h with excess Raney nickel and under an atmosphere of hydrogen. After 4 h the solution was filtered by vacuum filtration through Celite® and the solvent was removed under reduced pressure. The intermediate 5-amino-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-ol was then taken up in trimethyl orthoformate (20.0 mL, 183 mmol), and trifluoroacetic acid (0.05 ml, 0.649 mmol) was added. The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound (0.0246 g). LCMS m/z=220.0 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 2.10-2.20 (m, 2H), 2.31 (qd, J1=12.4 Hz, J2=4.7 Hz, 2H), 3.59 (td, J1=12.0 Hz, J2=1.9 Hz, 2H), 4.11 (dd, J1=11.8 Hz, J2=4.5 Hz, 2H), 4.80-4.90 (m, 1H), 6.98 (d, J=8.9 Hz, 1H), 8.18 (d, J=8.9 Hz, 1H), 8.56 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[BrH:18].[H][H]>C(O)C.[Pd]>[BrH:18].[OH:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: OCCOC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: OCCOC1CCNCC1

Procedure:
A solution of (B) (12 g) in ethanol (200 ml) was neutralized with an ethanolic solution of hydrogen bromide and hydrogenated in the presence of 10% palladium on carbon (2.4 g). After 5 hours the uptake of hydrogen ceased and the catalyst was removed by filtration. The filtrate was taken to dryness in vacuo to give (C) as a semicrystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17]CC2C=CC=CC=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Yield: 92.5 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoate (15.0 g, 32.1459 mmol) was dissolved in methanol (200 ml), added to a methanolic suspension (200 ml) of 10% palladium-carbon (1.0 g) and stirred for 16 hours at room temperature in a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (11.2 g, 29.7340 mmol, 92%).