Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:23][Si:24]([CH3:44])([CH3:43])[CH2:25][CH2:26][S:27]([N:30]=C1CCCCI1C1C=CC=CC=1)(=[O:29])=[O:28]>C(#N)C>[Br:1][C:2]1[C:3]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:17])(=[N:30][S:27]([CH2:26][CH2:25][Si:24]([CH3:44])([CH3:43])[CH3:23])(=[O:29])=[O:28])=[O:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: C[C@H](CO)Nc1nc(Nc2ccc(S(C)=O)cc2)ncc1Br
Reactant: C[Si](C)(C)CCS(=O)(=O)N=C1CCCCI1c1ccccc1
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NS(=O)(=O)CC[Si](C)(C)C)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
50 mg (0.13 mmol) of (R)-2-[5-bromo-2-{(RS)-4-methylsulfinyl-phenylamino}-pyrimidin-4-ylamino]-propan-1-ol in 3 ml of acetonitrile is mixed with a spatula tip full of CuPF6[CH3CN]4 (about 0.05 equivalent) and stirred for 30 minutes at room temperature. The mixture is cooled in an ice bath, mixed with 55 mg (0.13 mmol) of [N-(2-(trimethylsilyl)ethanesulfonyl)imino]phenyliodinane, and stirred for 4 hours at room temperature. It is cooled again in the ice bath, mixed with a spatula tip full of CuPF6[CH3CN]4 and with 22 mg (0.06 mmol) of [N-(2-(trimethylsilyl)ethanesulfonyl)imino]phenyliodinane and stirred for another 3 hours at room temperature. The mixture is evaporated to the dry state, and the remaining residue is purified by chromatography. 20 mg of (RS)-S-[4-({5-bromo-4-[(R)-(2-hydroxy-1-methylethyl)amino]pyrimidin-2-yl}amino)phenyl]-S-methyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide with a melting point of 194-197° C. is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH3:23]CCCP(CCCC)CCCC.[OH:36][CH2:37][C:38]1(CO)[CH2:40][CH2:39]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:21][C:19]1[CH:20]=[C:15]([O:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:12])=[O:13])[CH:16]=[C:17]([CH:18]=1)[O:22][CH2:23][CH:37]([CH:38]1[CH2:40][CH2:39]1)[OH:36]
Reactant: CCCCP(CCCC)CCCC
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Reactant: OCC1(CO)CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCC(O)C2CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 3-(2-methylsulfonylphenylsulfonyloxy)-5-methylphenol (6.85 g, 20.0 mmol), as prepared in step a of Example 8, tri-N-butylphosphine (6.1 g, 30 mmol) and 1,1-dihydroxylmethylcyclopropane (5.1 g, 50 mmol), as prepared in the preceding step, in tetrahydrofuran (200 mL) was added 1,1′-(azodicarbonyl)dipiperidine (7.6 g, 30 mmol). The mixture was stirred at room temperature overnight, hexane (300 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, the residue was purified by flash column chromatography (1:1 to 2:1 ethyl acetate/hexane) and by crystallization from ethyl acetate/hexane (1:5) to give the title compound as white solid (4.9 g, 57%). 1H-NMR (300 MHz, CDCl3) δ8.45 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 6.77 (br s, 3H), 3.82 (s, 2H), 3.59 (d, J=5.5 Hz, 2H), 3.45 (s, 3H), 2.23 (s, 3H), 0.61 (s, 4H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]([NH2:14])[CH2:4][CH2:3]1.C[C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1.[CH3:29][O:30][C:31]1[CH:40]=[C:39]2[C:34]([N:35]([CH3:43])[C:36](=[O:42])[CH:37]3[CH2:41][CH:38]32)=[CH:33][C:32]=1[CH:44]=O>>[CH3:29][O:30][C:31]1[CH:40]=[C:39]2[C:34]([N:35]([CH3:43])[C:36](=[O:42])[CH:37]3[CH2:41][CH:38]32)=[CH:33][C:32]=1[CH2:44][NH:14][CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[NH:7][CH:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Reactant: CC1CCC(N)C(c2ccccc2)N1
Agent: C[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Product: COc1cc2c(cc1CNC1CCC(C)NC1c1ccccc1)N(C)C(=O)C1CC21

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-Methyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S,)-6-methyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-methyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde [or (1S,1aR)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde or (1R, 1aS)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde].
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.[O:20]=[C:21]1[NH:25][CH2:24][CH2:23][N:22]1[CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[C:12]1([C:4]2[C:5]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[N:30][C:29]([NH:28][CH2:27][CH2:26][N:22]3[CH2:23][CH2:24][NH:25][C:21]3=[O:20])=[N:31][CH:3]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N=C(N)NCCN1CCNC1=O
Reactant: CN(C)C=C(C(=O)c1cccs1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1NCCN1CCNc1ncc(-c2ccccc2)c(-c2cccs2)n1
Temperature: 100 °C

Procedure:
3-(Dimethylamino)-2-phenyl-1-(thiophen-2-yl)prop-2-en-1-one (1 g, 3.88 mmol) in N-methyl pyrrolidone (10 mL) was treated with 1-(2-(2-oxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (1 M solution in N-methyl pyrrolidone 5.82 mL, 5.82 mmol) and cesium carbonate (1.26 g, 3.88 mmol). The mixture was heated at 100° C. overnight. The reaction was then allowed to cool to room temperature and poured into cold water. The aqueous layer was extracted three times with dichloromethane. All the organic layers were combined and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and purified by flash chromatography using a gradient of 0 to 10% methanol in dichloromethane to obtain a yellow solid. Yield=1.2 g. MS (M+H)+ 366.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:18]
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: CNCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCc1ccccc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenyl-propane (1.5 g--see Preparation 4), 1-(N-methylamino)-3-phenylpropane (0.746 g), anhydrous potassium carbonate (1.38 g) and acetonitrile (50 ml) was heated under reflux for 48 hours and then concentrated in vacuo. Water (30 ml) was added to the residue and the mixture was extracted with dichloromethane (3×40 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) and then dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.93 g.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][NH:6][C:5](=[S:8])[NH:4][CH2:3]1.[CH2:9]([Br:11])[CH3:10].C(O)C>CCOCC>[BrH:11].[CH2:9]([S:8][C:5]1[NH:4][CH2:3][CH:2]([OH:1])[CH2:7][N:6]=1)[CH3:10]
Reactant: OC1CNC(=S)NC1
Reactant: CCBr
Solvent: CCO
Solvent: CCOCC
Product: Br
Product: CCSC1=NCC(O)CN1
Temperature: -10 °C

Procedure:
A mixture of 26.4 g of tetrahydro-5-hydroxy-2(1H)-pyrimidinethione, 30 ml of ethyl bromide and 250 ml of ethanol was refluxed for 7 hours, clarified, diluted with 250 ml of ether and cooled to -10° C. The solid was crystallized twice from ether, giving 19.5 g of 2-(ethylthio)-1,4,5,6-tetrahydro-5-pyrimidinol, hydrobromide, mp 106°-108° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][C:21]([N:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:34]2[CH:33]=[CH:32][C:31]([N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]3[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=3)=[CH:36][CH:35]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccccc3)cc2)OC1(C)C
Reactant: Cc1cnc(Cl)c(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)c(C)n1
Temperature: 50 °C
Yield: 30 %

Procedure:
Next, there were put 0.36 g of 2-chloro-3,5-dimethylpyrazine, 0.92 g of 4,4,5,5-tetramethyl-2-(4-diphenylaminophenyl)-1,3,2-dioxaborolane obtained in Step 1, 0.26 g of sodium carbonate, 0.011 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile in a recovery flask equipped with a reflux pipe. The air in the flask was replaced by argon. This reaction container was heated by microwave irradiation (2.45 GHz, 100 W) for 20 minutes. After that, the reaction container was cooled to 50° C. or lower, water was added to the reaction solution, and the organic layer was subjected to extraction with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled, and the obtained residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane and ethyl acetate as a developing solvent, thereby obtaining the objective pyrazine derivative Hdmdpappr (white powder, 30% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, produced by CEM Corporation). The synthesis scheme of Step 2 is shown by (b-2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)CC)C.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C@H:57]1[CH2:60][N:59]([C:61]([NH:63][S:64]([NH:67][NH:68][C:69]([NH:71][C:72]2[CH:77]=[CH:76][C:75]([OH:78])=[C:74]([OH:79])[CH:73]=2)=[O:70])(=[O:66])=[O:65])=[O:62])[C:58]1=[O:80].C(OCC)(=O)C.Cl>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][C:13]([CH3:14])([CH3:15])[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:8]([NH:56][CH:57]2[CH2:60][N:59]([C:61]([NH:63][S:64]([NH:67][NH:68][C:69]([NH:71][C:72]3[CH:77]=[CH:76][C:75]([OH:78])=[C:74]([OH:79])[CH:73]=3)=[O:70])(=[O:66])=[O:65])=[O:62])[C:58]2=[O:80])=[O:10])[N:6]=1
Reactant: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)Nc2ccc(O)c(O)c2)C1=O
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)NNC(=O)Nc2ccc(O)c(O)c2)C1=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Into a -30° C. cold mixture of 0.66 g (1.5 mmol) of (Z)-2-amino-α-[[1-(diphenylmethoxycarbonyl)-1-methylethoxy]imino]-4-thiazoleacetic acid in 13 ml of dry dimethylformamide, 0.63 ml (4.5 mmol) of triethylamine was dropped, followed by 0.33 ml (1.5 mmol) of diphenylchlorophosphate. After stirring at -30° C. for 1 hour, 0.42 ml (3.0 mmol) of triethylamine was dropped in, followed by the addition of 0.80 g (1.5 mmol) of (S)-3-amino-1-[[[[2-[[(3,4-dihydroxyphenyl)amino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxoazetidine. The mixture was stirred for 2 hours at -10° C. and an additional 2 hours at 0° C. The solvent was removed in vacuo and the residue was taken up in a few ml of ethyl acetate and ice water. The pH of the mixture was corrected to pH=2 the addition of dilute hydrochloric acid. The insoluble material was collected by suction1) and stirred with a few ml of ethyl acetate until it became crystalline; yield after drying in vacuo: 0.31 g. This material was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=[O:13].C1CCN2C(=NCCC2)CC1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:13][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccc2ccccc2c1)OCc1ccccc1
Yield: 100.5 %

Procedure:
To a stirred solution of 2-naphthylacetic acid (1 g, 5.4 mmol) in acetonitrile (10 mL) were added DBU (0.97 mL, 6.4 mmol) and benzyl bromide (0.77 mL, 6.4 mmol). After 3 hours the mixture was concentrated, and the residue was taken up in ethyl acetate. The organic phase was washed with 10% citric acid, 10% NaHCO3 and brine, dried (MgSO4), and concentrated to give 2-naphthylacetic acid benzyl ester as a white solid (1.5 g, 100%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:52][CH2:51][C:16]([CH3:53])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:50])[O:23][C:24]2[CH:25]=[CH:26][C:27]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:53])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:50])[O:23][C:24]2[CH:25]=[CH:26][C:27]([O:45][C:46]([F:48])([F:49])[F:47])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:51][CH2:52]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(OC(F)(F)F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C)-c1cccc(c1)-c1cc(OC(F)(F)F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 15 %

Procedure:
Prepared in 15.0% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,5,22,28-tetramethyl-17-(trifluoromethoxy)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.19 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.37-7.30 (m, 3H), 7.29-7.24 (m, 1H), 6.01 (br. s., 1H), 4.70 (br. s., 1H), 3.85 (t, J=10.8 Hz, 1H), 3.64 (t, J=11.6 Hz, 1H), 3.46 (br. s., 2H), 3.10 (d, J=8.4 Hz, 1H), 2.63 (d, J=8.8 Hz, 1H), 2.51 (br. s., 3H), 2.31 (s, 3H), 1.93-1.51 (m, 10H), 1.19 (s, 3H), 1.16 (s, 9H), 1.12 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 724.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][CH2:17][NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN1CCCC1=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][CH2:17][NH:18][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][N:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reactant: NCCc1cc(Br)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)nc1
Temperature: 120 °C
Yield: 21.1 %

Procedure:
A mixture of 2-(2-aminoethyl)-4-bromophenyl benzyl ether (3 g), tert-butyl 2-chloro-5-pyridinecarboxylate (2.1 g) (prepared from the acid by standard procedures), and potassium carbonate (1.4 g) in N-methylpyrrolidone (20 ml) was heated at 120° C. for 16 hours. To the reaction mixture was added diethyl ether (200 ml) and water (200 ml), the layers separated, the organic layer washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate mixtures (100:0, 95:5) to give tert-butyl 2-[N-(2-benzyloxy-5-bromophenethyl)amino]-5 -pyridinecarboxy late (1.0 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][C:35]5[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=5[F:42])=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:44])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:53])=[N+]=[N-].N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.CO>[NH2:1][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][C:35]5[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=5[F:42])=[CH:28][CH:29]=4)[CH2:22][CH2:21][N:20]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[O:44])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:53]
Reactant: [N-]=[N+]=NCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21
Reaction time: 16 h

Procedure:
A solution of 0.660 g of benzyl 3-[4-(2-azidoethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}piperidine-1-carboxylate in 2.5 ml of tetrahydrofuran and 0.55 ml of water is admixed at room temperature with a solution of 0.55 ml of 25% conc. ammonia in 2.4 ml of methanol. After 0.357 g of triphenylphosphine has been added, the reaction mixture is stirred at mom temperature over 16 hours. The reaction mixture is poured onto water (40 ml) and extracted with tert-butyl methyl ether (3×40 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.31 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.01.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH:24]([F:27])[CH2:23][CH2:22]2)[CH2:5][CH2:4]1.CO>[Ni].C1COCC1>[F:29][C:2]([F:1])([F:30])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH:24]([F:27])[CH2:23][CH2:22]2)[CH2:7][CH2:8]1
Reactant: Nc1cc(N2CCC(F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CCC(F)CC2)cc1N
Reaction time: 1 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-(4-fluoro-piperidinyl)-4-amino-5-nitro-benzoic acid amide (150 mg, 0.35 mmol), Ra—Ni (15 mg), MeOH (2 mL) and THF (10 mL) is stirred under 50 psi H2-atmosphere for 1 h. The mixture is filtered and concentrated.
Reaction SMILES: F[C:2](F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[C:41](N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[C:52]1([CH:40]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:41][CH2:2][N:24]2[CH2:25][C@@H:26]3[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]3[CH2:23]2)[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCC(c3ccccc3)c3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3,3-diphenylpropanol for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.59 (dd, J=2.9, 7.0, 1H), 7.65 (d, J=8.1, 2H), 7.46 (d, J=7.2, 1H), 7.44-7.37 (m, 4H), 7.33 (tt, J=3.7, 7.7, 6H), 7.28-7.24 (m, 1H), 7.23-7.18 (m, 1H), 4.44-4.34 (m, 1H), 4.28 (d, J=7.2, 1H), 4.20 (dd, J=5.4, 9.1, 1H), 3.24 (d, J=10.4, 1H), 2.93 (dd, J=2.4, 9.0, 0.5H), 2.71-2.61 (m, 1H), 2.56 (dd, J=2.7, 9.2, 0.5H), 2.54-2.50 (m, 0.5H), 2.50-2.43 (m, 0.5H), 2.43-2.36 (m, 0.5H), 2.35-2.28 (m, 3H), 2.24 (tt, J=5.1, 10.0, 2H), 2.18-2.07 (m, 2H), 1.94-1.83 (m, 1H), 1.82-1.74 (m, 0.5H), 1.68 (td, J=7.0, 14.3, 0.5H), 1.47-1.37 (m, 1H), 1.37-1.29 (m, 0.5H), 1.22 (dd, J=4.6, 6.4, 3H), 0.71 (dd, J=1.7, 6.7, 3H); MS (ESI+) m/z 481 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 94.7 %

Procedure:
Prepared from (2-amino-4-thiazol-2-ylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G11) (89 mg, 0.28 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem. 1978, 25) (74 mg, 0.34 mmol) according to the general procedure K. Obtained as a light yellow solid (129 mg).