Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH:8]3[CH:13]([CH:14]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH2:15]2)[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:6][C:5]=1[O:26][CH3:27])([CH3:3])=[CH2:2]>[Pd].O>[CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH:8]3[CH:13]([CH:14]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[CH2:15]2)[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:6][C:5]=1[O:26][CH3:27])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc2c(cc1OC)C1CCCCC1C(c1ccc(OC)cc1)C2
Agent: [Pd]
Solvent: O
Product: COc1ccc(C2Cc3cc(C(C)C)c(OC)cc3C3CCCCC23)cc1
Yield: 91.4 %

Procedure:
Combine 7-Isopropenyl-6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (0.14 g, 0.39 mmol) and 10% Pd/C (0.13 g) and reduce at 50 psi of H2O.N. Filter catalyst and remove solvent in vacuo to yield the titled compound (0.13 g, 93%). 1H NMR (CDCl3): 7.28 (d, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.92 (d, J=8.8 HZ, 2H), 6.89 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.25 (m, 4H), 2.85 (m, 1H), 2.5 (m, 1H), 2.06 (m, 1H), 1.8-1.1 (m, 13H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[NH:6]1[CH2:11][CH2:10][C:9]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1.[OH-].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>OS(O)(=O)=O>[N+:1]([C:17]1[CH:16]=[C:15]2[C:20]([C:9]3([CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[CH:12]=[CH:13][NH:14]2)=[CH:19][CH:18]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc2c(c1)NCCC21CCNCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)NC=CC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
KNO3 (69.97 mg, 0.69 mmol) was added portion-wise to a suspension of 1,2,3,4-tetrahydroquinolin-4-spiro-4′-piperidine (133 mg, 0.66 mmol) in 98% H2SO4 (2 mL) at 0° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for additional 2 h. The mixture was then poured into cracked ice and basified with 10% NaOH to pH˜8. Boc2O (172 mg, 0.79 mmol) was added dropwise and the mixture was stirred at room temperature for 1 h. The mixture was then extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated to yield crude 7′-nitro-spiro[piperidine-4,4′(1′H)-quinoline], 2′,3′-dihydro-carboxylic acid tert-butyl ester (230 mg), which was used in the next step without further purification.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]>>[CH2:9]([N:11]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCNc1ccccc1
Reactant: O=C1CCCCC1Cl
Product: CCN(c1ccccc1)C1CCCCC1=O

Procedure:
First step is chlorinating cyclohexanone to form 2-chlorocyclohexanone. The obtained 2-chlorocylohexanone is then reacted with N-ethyl aniline to form 2-(N-ethyl anilino)cyclohexanone which is further heated to reflux with simultaneous water removal to complete the cyclization which results in formation of 9-ethyl-tetrahydrocarbazole. Excess of N-ethyl aniline is then removed by treatment with conc. hydrochloric acid and water wash. The obtained organic layer is then washed to make acid free and concentrated to get 9-ethyl tetrahydrocarbazole as a viscous liquid. The crude product is taken for next step without further treatment. N-ethyl aniline is regenerated from aqueous hydrochloride solution by basification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:25](I)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:25]([O:21][C:16]1[C:15]([N+:22]([O-:24])=[O:23])=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[N:19]=[C:18]([CH3:20])[N:17]=1)[CH3:26]
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(C)nc(N2CCN(c3ccc(F)cc3)CC2)c1[N+](=O)[O-]

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) was treated with ethyliodide and potassium carbonate in N,N-dimethylformamide at room temperature to yield the 4-ethoxy-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-pyrimidine as a light yellow solid; m.p. 116-119° C.; MS: [M+H]+=362; and the 3-ethyl-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one as yellowish solid; m.p. 126-128° C.; MS: [M+H]+=362.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].O.[OH:8][CH:9]1[CH2:13][C:12](=O)[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:10]1[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.C(O)C>[OH:8][CH:9]1[CH2:13][C:12](=[N:2][NH:3][C:4]([NH2:6])=[O:5])[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:10]1[CH:24]=[CH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NNC(N)=O
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: NC(=O)NN=C1CC(O)C(C=Cc2ccccc2)=C1CCCCCCC(=O)O
Reaction time: 16 h

Procedure:
A solution of 2 parts of semicarbazide hydrochloride in 3 parts of water is combined with a solution of 2 parts of 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid dissolved in 2.95 parts of pyridine and 15.8 parts of ethanol. The resulting solution is allowed to stand for about 16 hours at room temperature. Then the crystalline precipitate is filtered, washed with an aqueous 80% ethanol solution and then with water. After drying, the material is recrystallized from boiling isopropanol to afford pale yellow crystals of 3-hydroxy-5-semicarbazono-2-styrylcyclopent-1-eneheptanoic acid, melting at about 208°-210°, and displaying, in potassium bromide, an infrared absorption spectrum with maxima at about 3480, 1720, 1693 and 1586 reciprocal centimeters. That compound further displays, in methanol, an absorption band in the ultraviolet spectrum at about 355 millimicrons with a molecular extinction coefficient of about 54,000 and is characterized by the following structural formula ##SPC20##
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C@:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[C@H:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:10][CH2:9]1.[CH3:45][S:46](Cl)(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl>[CH3:45][S:46]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[CH:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:12][CH2:13]1)(=[O:48])=[O:47]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCNCC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)NC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), methanesulfonyl chloride (14 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the mixture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crude which was chromatographed on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid. 53 mg.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC=CC=1.C(P)=CC=C.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[C:20]([CH2:22][C:23]([O:25][CH2:26][CH2:27][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])#[N:21]
Reactant: CCOC(=O)CC#N
Reactant: Ic1ccccc1
Agent: C=CC=CP
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Brc1ccccc1
Solvent: CC#N
Product: N#CCC(=O)OCCc1ccccc1

Procedure:
The general procedure (acetonitrile, 82° C., 12 hours with iodobenzene; 30 hours in the case of bromobenzene) was followed using 9.52 mg (0.05 mmol) of copper iodide CuI, 31.4 mg (0.1 mmol) of (Z)-cinnamic butadienylphosphine of example A-1-1, 80 ml (0.75 mmol) of ethyl cyanoacetate, 318 mg (1.5 mmol) of potassium phosphate (K3PO4), 56 μl (0.5 mmol) of iodobenzene (53 μl of bromobenzene) and 500 μl of acetonitrile. The residue obtained after treatment (dichloromethane/water extraction) was purified by chromatography on a silica column (gradient: hexanes/CH2Cl2 100:0 to 75:25).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[O:10][C:11]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:12][C:13]=2[C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[CH2:18][CH2:17]3)[CH:6]=[CH:5][N:4]=1.O>[Ni].C(O)C>[N:25]1([CH2:24][C:11]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][N:8]=3)=[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[CH2:18][CH2:17]4)[CH:12]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CSc1nccc(-c2oc(CN3CCCCC3)cc2-c2ccc3c(c2)CCC3=O)n1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: O=C1CCc2cc(-c3cc(CN4CCCCC4)oc3-c3ccncn3)ccc21
Temperature: 25 °C
Yield: 104.9 %

Procedure:
A mixture of the product of Step 4 (0.135 g, 0.329 mmol) and Raney nickel (0.262 g of an aqueous suspension) in ethanol (15 ml) and water (5 ml) was heated at 100° C. for 20 hours. The mixture was then cooled to room temperature, filtered through celite and the filtrate reduced in vacuo. The residue was then purified by chromatography on silica gel eluting with a mixture of 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95), to furnish the title compound (0.016 g, 0.345 mmol); MS(ES+) m/e 374 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:12][C:11]1[CH:13]=[CH:14][C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:22]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(C2CCNCC2)cc1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 60 °C
Yield: 12.6 %

Procedure:
A mixture of 4-(piperidin-4-yl)aniline hydrochloride (14.10 mmol, 3 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (14.10 mmol, 4.75 g) and potassium carbonate (42.3 mmol, 5.85 g) in acetonitrile was heated to 60° C. (heating block temperature) for 20 hours. The reaction was concentrated under reduced pressure and dichloromethane was added. The mixture was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (770 mg). MS (ESI) m/z 433.3 [M+H]+
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH:22]=[C:21]([C:23]([OH:25])=O)[N:20]=[N:19]1)#[N:11].NC1C=CC=CC=1C#N.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:57][CH2:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([O:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([C:74]([F:77])([F:76])[F:75])[CH:69]=2)[CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.O>[O:60]=[C:59]([N:61]1[CH2:62][CH2:63][CH:64]([O:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([C:74]([F:77])([F:75])[F:76])[CH:69]=2)[CH2:65][CH2:66]1)[CH2:58][NH:57][C:23]([C:21]1[N:20]=[N:19][N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:10]#[N:11])[CH:22]=1)=[O:25]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: N#Cc1ccccc1-n1cc(C(=O)O)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#Cc1ccccc1N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cc(C(=O)NCC(=O)N2CCC(Oc3cccc(C(F)(F)F)c3)CC2)nn1
Reaction time: 0.03 h
Yield: 37.6 %

Procedure:
DIPEA (163 mg, 1.26 mmol) was added to a stirred solution of 1-(2-cyano-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (60 mg, 0.28 mmol) (prepared by the method used for the synthesis of Intermediate 64, starting from 2-aminobenzonitrile) in DMF (5 mL) followed by HOBt (41 mg, 0.3 mmol) and EDCI (134 mg, 0.7 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (104 mg, 0.3 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was then added and the solid was collected. The solid obtained was purified by column chromatography (using 60-120 silica gel and 30-70% EtOAc in hexane as eluent) to afford 52 mg (37.6% Yield) of 1-(2-cyano-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 499, 96.38%. 1H NMR (300 MHz, DMSO-d6): δ 9.3 (s, 1H), 8.64 (t, 1H), 8.22 (d, 1H), 8.02 (t, 2H), 7.84 (t, 1H), 7.6 (t, 1H), 7.4 (t, 3H), 4.9 (m, 1H), 4.3 (d, 2H), 4.0 (s, 1H), 3.8 (s, 1H), 3.5 (s, 1H), 2.1 (t, 2H), 1.8 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[F:10].C(NC(C)C)(C)C.[Li].[C:19](=[O:21])=[O:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])=[C:6]([CH:7]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: Fc1ccc(Br)c(F)c1F
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 1-bromo-2,3,4-trifluorobenzene (1) (5.0 mL, 41.7 mmol) in THF (120 mL) was added lithium diisopropylamine (2.0 M solution, 21 mL, 42 mmol) at −78° C. After stirring for 1 hour at −78° C., the mixture was added to a solution of CO2 in THF (1 L). The dry-ice bath was removed and the reaction mixture stirred overnight at room temperature. The reaction mixture was quenched with 10% aqueous HCl (835 mL), concentrated, and washed with ether (250 mL). The combined organics were washed with 5% aqueous NaOH (300 mL) and water (100 mL, pH 12). The aqueous layer was acidified (pH 0) with concentrated HCl. The resulting suspension was extracted with ether (2×300 mL), dried over MgSO4, filtered, concentrated under reduced pressure to afford 7.70 g (72% yield) of the desired product (2).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)([O-:18])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NCc2cccc([N+](=O)[O-])c2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of tert-butyl N-(4-aminocyclohexyl)carbamate (25 g, 117 mmol, 1.0 eq) and 3-nitrobenzaldehyde (18 g, 117 mmol, 1.0 eq) in MeOH (500 mL) was added NaBH(OAc)3 (50 g, 234 mmol, 2.0 eq) by portions. Then the resulting mixture was stirred overnight at 30° C. LC-MS indicated complete conversion. The solvent was removed under vacuum and the residue was purified by column chromatography (DCM:MeOH=15:1) to provide tert-butyl N-(4-[(3-nitrobenzyl)amino]cyclohexyl)carbamate (33 g, 83%) as a yellow solid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.N(O)=O.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19].[OH-].[Na+].O>CC(O)CC>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cccc(NC(=N)N)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: O=NO
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)O
Solvent: O
Product: CCOC(=O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Yield: 71 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one (1.72 g, 8.18 mmol), 3-ethoxycarbonyl-phenyl-guanidine nitrite (2.21 g, 8.18 mmol), sodium hydroxide (0.327 g, 8.18 mmol) in 2-butanol (40 mL) is heated to reflux for 24 hours before cooling to room temperature with the addition of water (40 mL). The solid is collected by filtration, washed with water and 2-propanol, and dried to give N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (2.06 g); ESI-MS (m/z): 355.1 (M++H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)cc1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-methoxyphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (41%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH3:24][S:25][C:26]1[CH:27]=[N:28][N:29]([C:31]2([C:34](=N)OCC)[CH2:33][CH2:32]2)[CH:30]=1.C(O)(=O)C.C(N(CC)CC)C>C(O)C>[CH3:24][S:25][C:26]1[CH:27]=[N:28][N:29]([C:31]2([C:34]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH2:32][CH2:33]2)[CH:30]=1
Reactant: CCOC(=N)C1(n2cc(SC)cn2)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1cnn(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)c1
Temperature: 110 °C

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (189 mg, 0.653 mmol) and ethyl 1-(4-(methylthio)-1H-pyrazol-1-yl)cyclopropanecarbimidate (157 mg, 0.697 mmol) in ethanol (1.86 mL) was added acetic acid (0.372 mL) followed by triethylamine (0.545 mL, 3.91 mmol). The reaction mixture was heated to 110° C. for 2 h. The mixture was cooled to room temperature, the solvent was removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of ammonium chloride (100 mL) and dichloromethane (200 mL). The aqueous layer was extracted with dichloromethane (100 mL) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 452.2; HPLC retention time 2.11 min (Method A).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].ClCCl>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[2-(1-t-Butoxycarbonylpiperidin-4-yl)phenyl]methanesulfonamide (488 mg) was dissolved in trifluoroacetic acid-dichloromethane (10%, 50 mL) and stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure to give the title compound as a colourless gum (501 mg), δH (CDCl3) 1.97 (4H, br m), 3.03 (3H, s), 3.16 (2H, m), 3.48 (1H, m), 3.68 (2H, m), 7.25-7.43 (4H, m), 8.01 (1H, br s).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[CH:28][C:27]=1[CH3:41])=[O:25].C(OCC)(=O)C>O1CCCC1.O>[CH3:41][C:27]1[CH:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)[CH:30]=[CH:31][C:26]=1[C:24](=[O:25])[CH2:23][C:11]([CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Reactant: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.3 %

Procedure:
To a cold suspension (0-5° C.) of 95% sodium hydride (3.53 g, 13.0 mmol) in dry tetrahydrofuran (30 mL) was slowly added diethyl 2-phenylethylmalonate (3.53 g, 13 mmol). The ice bath was removed and the reaction mixture was stirred at rt for 45 minutes. A solution of 2-bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone (4.06 g, 12.0 mmol) in dry tetrahydrofuran (50 mL) was slowly added, and the resulting mixture was stirred at rt for about 70 h. Ethyl acetate (80 mL) and water (20 mL) were added, and the layers were separated. The organic layer was washed with water (2×30 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a dark, brown oil. This material was purified by flash chromatography (10:90 ethyl acetate/hexane) to give diethyl 2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate as a light yellow oil (5.30 g, 82% yield). LC-MS ret. time 4.01 min, m/z 517.9 (MH+); 1H NMR (CDCl3) δ 1.23-1.35 (m, 6H), 2.41-2.50 (m, 2H), 2.56 (s, 3H), 2.59-2.66 (m, 2H), 3.71 (s, 2H), 4.21-4.32 (m, 4H), 7.13-7.19 (m, 3H), 7.22-7.30 (m, 2H), 7.49-7.55 (m, 2H), 7.73-7.82 (m, 3H), 8.31 (d, 2H).