Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH3:10])[N:12]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(Br)nc1
Reactant: Cn1ccc(N)n1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccn(C)n2)nc1
Temperature: 80 °C
Yield: 55 %

Procedure:
2-Bromo-5-methoxy-pyridine (0.97 mmol), sodium-tert.-butylate (1.5 eq.), and 1-methyl-1H-pyrazole-3-amine (1.3 eq.) are dissolved in degassed dioxane (2 ml) and heated to 80° C. Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium (II) (5 mg) in degassed dioxane (1 ml) is added and the reaction is heated for 20 hours at 110° C. The reaction is quenched with ethylacetate/methanol (30 ml, 9:1) and filtrated over celite. The solvent of the filtrate is removed in vacuo. (5-Methoxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine (“A24”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as colorless powder in a yield of 55%; HPLC (method C): 1.09 min; LC-MS (method A): 0.73 min, 205.0 (M+H+);
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([CH3:25])([CH2:14][O:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:25][C@:10]1([CH2:14][O:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@]1(COCCOC2CCCCO2)CCCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@]1(COCCOC2CCCCO2)CCCNC1
Yield: 83.6 %

Procedure:
(S)-1-Benzyl-3-methyl-3-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]piperidine (1.14 g, 3.3 mmol) in MeOH (11 ml) was added to a suspension of Pd/C (0.23 g) in MeOH (11 ml), followed by ammonium formate (1.03 g, 16.4 mmol). The mixture was refluxed for 2 h, after which it was cooled and filtered through Celite. The catalyst was washed with DCM and the combined organic phases were evaporated to dryness. To the residue was added brine (15 ml) and the solution was extracted with EtOAc (3×30 ml). The extracts were combined, dried, filtered and evaporated to yield 0.71 g of the debenzylated product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=C(C=CC=1)N)#N.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]1=[O:38]>>[CH:4]1([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=4)[C:27]#[N:28])[N:18]=3)[CH:13]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:12]2=[O:38])[CH2:3][CH2:1]1
Reactant: N#Cc1cccc(N)c1
Reactant: CN1CCN(c2ccnc(Nc3cccc(C#N)c3)n2)C(c2ccccc2)C1=O
Product: N#Cc1cccc(Nc2nccc(N3CCN(CC4CC4)C(=O)C3c3ccccc3)n2)c1
Yield: 72 %

Procedure:
Intermediate 4, (0.20 g, 0.58 mmol) and 3-cyanoaniline (0.14 g, 1.17 mmol) were reacted together following the procedure detailed for the compound of Example 2 which gave the title compound as a pale yellow solid (0.18 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:38])[C:32]3[N:36]=[CH:35][NH:34][C:33]=3[CH:37]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:38])[C:32]6[N:36]=[CH:35][NH:34][C:33]=6[CH:37]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
47 mg (0.17 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 45 mg (0.17 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-4-methyl-1H-benzimidazole and 0.06 mL (0.34 mmol) DIPEA were combined in 2.0 mL DMF and stirred for 48 h at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24]OS(C)(=O)=O)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOS(C)(=O)=O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCn1ccnc1

Procedure:
To a solution of 0.218 g methyl 8-(p-chlorophenylsulfonamido)-4-(2-methylsulfonyloxyethyl)-octanoate in 2 ml dimethylformamide is added 0.101 g imidazole and then the solution is heated at 100° for 8 h. The mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water (2×20 ml), dried, filtered and evaporated to give an amber oil which is purified by preparative thin layer chromatography using ethyl acetate as eluent to give methyl 8-(p-chlorophenylsulfonamido)-4-[2-(1-imidazolyl)ethyl]-octanoate as a yellow oil.
Reaction SMILES: [B:1]1(B2OCC(C)(C)CO2)[O:6]CC(C)(C)C[O:2]1.C([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26](OS(C(F)(F)F)(=O)=O)[C:27]=2[O:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:34][CH:33]=2)[CH:22]=1)(=O)C.[F-].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.N(CCO)CCO.[ClH:83]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[ClH:83].[OH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:34][CH:33]=1)=[C:26]([B:1]([OH:6])[OH:2])[CH:25]=[CH:24]2
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: CC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCOCC
Solvent: OCCNCCO
Product: OB(O)c1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Reaction time: 1 h

Procedure:
Add bis(neopentyl glycolato)diboron (4.2 g, 18.59 mmol), 5-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl acetate (2.33 g, 4.21 mmol), palladium (II) acetate (0.199 g, 886.38 μmol), cesium fluoride (5.21 g, 34.30 mmol), tricyclohexylphosphine (0.41 g, 1.40 mmol) and acetonitrile (50 mL) to a round bottom flask. Reflux the mixture with stirring for 1 hour under a nitrogen atmosphere. Cool the mixture, filter and wash the solids with acetonitrile. Concentrate the combined filtrate and washes. Suspend the resulting residue in diethyl ether (40 mL) and sonicated for 30 minutes. Remove the precipitate by filtration and concentrate the filtrate to obtain the crude intermediate. Add diethanolamine (405.25 μL, 4.21 mmol) to a solution of the crude intermediate in ether (50 mL). Stir the mixture for 1 hour. Decant the organic layer and dissolve the remaining residue in methanol (20 mL) and 10 mL of water. Add concentrated HCl (2 mL; 24 mmol) and stir the resulting mixture for 16 hours. Concentrate the mixture to remove MeOH. Extract the aqueous residue 3 times with dichloromethane. Combine the extracts, dry over sodium sulfate, filter, and concentrate to dryness. Purify the residue by flash chromatography on silica to obtain the title compound. (0.6 g, 1.47 mmol).
Reaction SMILES: [CH2:1]([P:8](=[O:11])(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CN(C=O)C>ClCCl>[CH2:1]([P:8]1(=[O:11])[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(O)(O)Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=P1(Cc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
Under nitrogen atmosphere, to a mixture of magnesium (3.2 g) and a piece of iodine in diethylether (20 ml) was dropwise added to a solution of 1,5-dibromopentane (13.21 g) and 1,2-dibromoethane (1.21 ml) in diethylether (80 ml) at 40° C. for 1 hour. The mixture was refluxed for 1 hour, cooled to room temperature and allowed to stand for 2 hours. The upper layer of diethylether was removed through cannula, to obtain the di-Grignard reagent, which was dissolved in dichloromethane (250 ml). The resulting di-Grignard reagent as it is was used for the following reaction. To benzylphosphonic acid (10.0 g) was added thionyl chloride (30 ml) and then a drop of DMF, and the mixture was refluxed for 3 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane (210 ml), and the mixture was cooled to 0° C. To the mixture was dropwise added a solution of the above di-Grignard reagent in dichloromethane, which was cooled to 0° C., through cannula for 1 hour, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture were added 10% ammonium chloride solution (100 ml) and saturated sodium chloride solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3→1:2) to give 1-benzylphosphorinane-1-oxide (5.39 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([CH2:11][C:12]1[S:16][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([CH2:11][C:12]1[S:16][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)s1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)s1)C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.5 %

Procedure:
2-(2-tert-Butoxycarbonylamino-thiazol-5-ylmethyl)-malonic acid diethyl ester (158 mg; 0.43 mmol) was dissolved in ethanol (1 mL) and THF (0.5 mL), and a solution of KOH (24 mg; 0.43 mmol) in ethanol (0.14 mL) was added at 0° C. The reaction mixture was stirred at room temperature for 96 hours, and then poured onto ice-water. The aqueous phase was extracted with diethyl ether, acidified to pH 3 by addition of 0.5 M HCl, and extracted with diethyl ether. The combined organic phases were dried and concentrated to yield 2-(2-tert-butoxycarbonylamino-thiazol-5-ylmethyl)-malonic acid monoethyl ester (97 mg, 66.4%).
Reaction SMILES: CC1C=CC(S(N[C@H](CC#C)C)(=O)=O)=CC=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:20]=[C:21]([S:25]([NH:28][C@H:29]([CH2:31][C:32]#[C:33][Si](C)(C)C)[CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[CH3:30][C@H:29]([NH:28][S:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:39])([F:17])[F:38])[CH:20]=1)(=[O:26])=[O:27])[CH2:31][C:32]#[CH:33]
Reactant: C[C@@H](CC#C[Si](C)(C)C)NS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: C#CC[C@H](C)NS(=O)(=O)c1ccc(C)cc1
Product: C#CC[C@H](C)NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
Proceeding as described for (54), but using (S)-3-(trifluoromethyl)-N-(5-(trimethyl-silyl)pent-4-yn-2-yl)benzenesulfonamide afforded (S)—N-(pent-4-yn-2-yl)-3-(trifluoromethyl)-benzenesulfonamide (55). MS (m/z): 292.1 (M+H) (Calc'd for C12H12F3NO2S: 291.29).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])[CH2:35][CH2:34]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Clc1ccccc1N1CCNCC1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 78 %

Procedure:
Phenyl N-(2-methoxyquinoline-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>>[Si:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)[Si](C)(C)OCCCCCCNC1CCCCC1
Temperature: 80 °C
Reaction time: 60 h
Yield: 90.6 %

Procedure:
In a sealed tube was charged with ((6-bromohexyl)oxy)(tert-butyl)dimethylsilane (2.35 mL, 8.45 mmol), cyclohexanamine (1.95 mL, 16.9 mmol), potassium carbonate (2.34 g, 16.9 mmol), and acetonirile (6 mL). The mixture was stirred at 80° C. for 2.5 days and filtered through a pad of celite. The solution was concentrated and purified on silica gel with a eluent of Methanol (2N NH3):methylene chloride from 0:1 to 5:95 to give a clear oil (2.4 g, 90%). 1H NMR (300 MHz, CDCl3): δ 3.55 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H), 2.42-2.28 (m, 1H), 1.89-1.78 (m, 2H), 1.74-1.62 (m, 2H), 1.62-1.52 (m, 2H), 1.52-1.36 (m, 4H), 1.36-1.22 (m, 5H), 1.22-0.92 (m, 5H), 0.85 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7](CC#N)=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16][N:17]([CH3:19])[CH3:18]>C1COCC1.O.[Pd](Cl)Cl>[Cl:5][C:6]1[C:7]([CH2:2][C:1]([NH2:4])=[O:3])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16][N:17]([CH3:19])[CH3:18]
Reactant: CC(N)=O
Reactant: CN(C)Cc1cccc2cc(Cl)c(CC#N)cc12
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc2cc(Cl)c(CC(N)=O)cc12
Reaction time: 18 h

Procedure:
Palladium(II)-chloride (4.3 mg, 0.024 mmol, 0.1 equiv) and acetamide (60 mg, 1.0 mmol, 4.2 equiv) were added to a solution of (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetonitrile in THF (0.75 ml) and water (0.25 ml). After 18 hours at room temperature, the reaction mixture was adsorbed on silica gel, concentrated to dryness, and purified via two flash columns. Since purification on silica gel failed to remove unreacted acetamide, the resulting mixture was used directly in the next step. MS (ES+): 277 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[CH2:11]=[O:12].[OH-].[K+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12])([O-:3])=[O:2]
Reactant: C=O
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1CCO
Temperature: 70 °C
Yield: 41.9 %

Procedure:
A mixture of 137 g (1 mole) of o-nitrotoluene, 60 g of paraformaldehyde and 400 ml of dimethyl formamide containing 0.5% by weight of water is heated to 70° C. under stirring. Thereafter 40 g of potassium hydroxide, covered with 100 ml dimethyl formamide, are added to the mixture at such a rate that the temperature of the reaction mixture does not increase above 120° C. The resulting mixture is stirred for 3 minutes at a temperature above 85° C., thereafter it is cooled and filtered through a sintered glass filter. The filtrate is acidified with hydrochloric acid to pH=3, filtered again, and the resulting filtrate is evaporated. 100 g of a residue, containing 80% by weight of 2-(o-nitrophenyl)-ethanol, are obtained. This residue is distilled in vacuo to obtain 70 g of 2-(o-nitrophenyl)-ethanol with a purity grade of 98%. 45 g of o-nitrotoluene are recovered. The product is analyzed by gas chromatography.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[CH:12]=[CH:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>C(O)C.C(OCC)C.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:17]=3)[CH:12]=[CH:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSC(=N)c1cccs1
Reactant: O=[N+]([O-])c1ccc2ccn(CCCCn3ccnc3)c2c1
Agent: [Pd]
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: N=C(Nc1ccc2ccn(CCCCn3ccnc3)c2c1)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
1-(4-(1H-imidazol-1-yl)butyl)-6-nitro-1H-indole (compound 166, 145 mg, 0.510 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (54.2 mg, 0.051 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (10% 2M NH3 in methanol/90% dichloromethane) shows complete conversion to compound 167, 1-(4-(1H-imidazol-1-yl)butyl)-1H-indol-6-amine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 167 is charged to a small, argon purged flask fitted with a magnetic stir bar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (189.1 mg, 0.663 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 20 hours, at which time the solution was diluted with diethyl ether (100 ml) resulting in the formation of a sticky solid which could not be isolated via filtration. As a result the product was washed off the funnel with methanol, combined with the filtrate and solvents evaporated to leave a crude residue. The residue was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated and the residue purified via chromatography on silica gel (2.5% 2M NH3 in methanol/97.5% dichloromethane) to yield yellow solid, compound 168 (101 mg, 54.5% yield); 1H-NMR (DMSO-d6) δ 7.74 (d, 1H, J=3.0), 7.60 (d, 1H, J=5.2), 7.56 (s, 1H), 7.45 (d, 1H, J=8.3), 7.21 (d, 1H, J=3.0), 7.13-7.06 (m, 2H), 6.92 (s, 1H), 6.85 (s, 1H), 6.59 (d, 1H, J=8.0), 6.42-6.30 (br, 2×m, 3H), 4.17-4.06 (m, 2H), 3.99-3.92 (m, 2H), 1.75-1.58 (m, 4H); MS (ESI+): 364 (M+1, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(CCNC2CCCCC2O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Oc2ccc(CCNC3CCCCC3O)cc2)nc1
Temperature: 25 °C

Procedure:
Heat a mixture of 4-[2-(2-hydroxycyclohexylamino)ethyl]phenol (152.6 mg, 0.65 mmol), 6-chloronicotinamide (84.6 mg, 0.54 mmol) and K2CO3 (186.7 mg, 1.35 mmol) in 3:1 DMF/toluene (4.0 mL) at 160° C. for 2 hours. Cool to room temperature and filter with thorough MeOH and CH2Cl2 wash. Concentrate the filtrate and remove DMF azeotropically with xylenes. Purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH (56.3 mg, 29%): MS ES+ 356.1 (M+H)+, HRMS calcd for C20H26N3O3 356.1974 (M+H)+, found 356.1966, time 0.37 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.23 min, 100% purity; Chiralpak AD 225 min, 60:40 EtOH/heptane at 1.0 mL/min, tR=5.55 min, 50% and tR=7.17 min, 50%; Anal. Calcd for C20H25N3O3.0.2CH2Cl2.0.2MeOH: C, 64.68; H, 6.97; N, 11.09. Found: C, 64.46; H, 6.84; N, 11.11.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:42][CH:41]=3)=[CH:38][CH:39]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)#[N:2]
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 300 mg (0.73 mmol) of methyl 4-[(4E)-3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-en-1-yl]benzoate in 30 ml of dry acetonitrile is mixed with 236.8 mg (0.87 mmol) of 4-(chloromethyl)-4′-(trifluoromethyl)biphenyl and 151 mg (1.09 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 331 mg (0.51 mmol, 70% of theory) of a solid are obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=3[N+:26]([O-])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Rh].C>[NH2:26][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:16]=1[CH2:15][NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12]1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(CNC2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Agent: [Rh]
Solvent: CO
Product: COC(=O)c1ccc(CNC2CCN(Cc3ccccc3)CC2)c(N)c1

Procedure:
A solution of 58.0 g (0.151 mol) of methyl 4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-nitrobenzoate in 800 ml of methanol was hydrogenated in the presence of 10 g of 5% rhodium/charcoal for 7 hours at room temperature. The catalyst was filtered off, the filtrate was evaporated down in vacuo. 50.0 g (93.7% of theory) of colourless crystals were obtained, which were further processed without any more purification.