Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:31][O:30][C:22]1[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=[C:20]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:10][CH:9]=2)[C:5]2[NH:4][C:3](=[O:2])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of 6.02 g of [2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 50 ml of DMF there were added 1.24 g of 2-hydrazinopyrimidine and 1.9 ml of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 50 ml of methanol and 5 ml of acetic acid. After then adding 3.4 g of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (3.317 g) as a light yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2[nH]1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Temperature: 60 °C
Yield: 37.7 %

Procedure:
To a solution of 2-[(2-Cyclopropylethyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (300 mg) in dry DMF (5 mL) was added anhydrous potassium carbonate (457 mg) and the mixture was heated at 60° C. for 1.5 h. The reaction was cooled to room temperature and tetrahydro-3-furanylmethyl methanesulfonate (164 mg) was added. The reaction was heated at 90° C. for 3.5 h and was then quenched into water (50 mL) and extracted with EtOAc (3×50 mL). The organics were separated, dried by passing through a hydrophobic frit and evaporated under reduced pressure to give a glassy solid. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to give the title compound (103.8 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]1.[CH3:16][C:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:23]([C:17]2([CH3:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:24])[CH2:9][CH2:8]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: NCCN1CCN(c2ncccn2)CC1
Solvent: CCN(CC)CC
Product: CC1(C(=O)NCCN2CCN(c3ncccn3)CC2)CCCCC1

Procedure:
The title compound was prepared from 2-(4-(2-pyrimidinyl)-1-piperazinyl)ethyl amine (1.50 g, 0.00724 mol), 1-methylcyclohexylcarboxylic acid chloride (1.16 g, 0.00722 mol) and triethylamine (1.1 mL, 0.80 g, 0.0079 mol) in the manner previously described to give 1.80 g (62%) of product, mp. 212°-220° C.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:17]3[C:18](=[O:33])[C@@H:19]([NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][CH:21]=[CH:22][CH2:23][C@@H:16]3[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C:6](=[O:34])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:17]3[C:18](=[O:33])[C@@H:19]([NH:24][C:25](=[O:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH:21]=[CH:22][CH2:23][C@H:16]3[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C:6](=[O:34])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)[C@@H]1CCC[C@H]2CC=CC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(NC(=O)[C@@H]2CCC[C@@H]3CC=CC[C@H](NC(=O)c4ccccc4)C(=O)N32)C(O)O1
Reaction time: 0.5 h

Procedure:
A solution of (4S,7S,11aS)-7-benzoylamino-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide, 45, (32 mg) in 10 mL of 1:1 acetonitrile/water is treated with 2 mL of trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford 21 mg of the desired product as a white solid. 1H NMR (CD3OD) δ 7.92 (d, J=7.0 Hz, 2H), 7.54 (m, 3H), 5.75 (m, 1H), 5.63 (m, 1H), 5.42 (dd, J=8.1, 4.8 Hz, 1H), 5.01 (d, J=6.2 Hz, 1H), 4.72 (m, 1H0, 4.65 (d, J=4.0 Hz, 0.5H), 4.64 (d, J=4.0 Hz, 0.5 H), 4.31 (m, 1H), 3.18 (m, 1H), 2.68 (m, 2H), 2.45 (m, 3H), 2.26 (br d, J=13.9 Hz, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.80 (br d, J=13.2 Hz, 1H), 1.61 (m, 2H); MS 442 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][C:6]([NH2:20])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:8]=2)[N:3]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[CH3:23][N:24]([CH:26]=[N:1][C:2]1[N:11]=[C:10]([N:12]=[CH:23][N:24]([CH3:26])[CH3:25])[C:9]2[C:4](=[N:5][C:6]([N:20]=[CH:23][N:24]([CH3:26])[CH3:25])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:8]=2)[N:3]=1)[CH3:25]
Reactant: Nc1nc(N)c2nc(-c3ccccc3Cl)c(N)nc2n1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1nc(N=CN(C)C)c2nc(-c3ccccc3Cl)c(N=CN(C)C)nc2n1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.5 gram (0.002 mole) of 2,4,7-triamino-6-(2-chlorophenyl)pteridine (prepared in Example 2) in 50 mL of N,N-dimethylformamide dimethylacetal was heated at reflux for about 5 hours. After this time the reaction mixture was cooled in an ice-bath, and a solid was collected by filtration. The solid was washed with diethyl ether, yielding, when dried, 0.5 gram of 2,4,7-tri-(dimethylaminomethyleneamino)-6-(2-chlorophenyl)pteridine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C1(S[C:8]([C@H:15]2[NH:18][C:17](=[O:19])[C@@H:16]2[C@H:20]([O:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:21])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])C=CC=CC=1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl.C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10]([C:8]([C@H:15]1[NH:18][C:17](=[O:19])[C@@H:16]1[C@H:20]([O:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])[CH3:21])=[CH2:9])=[O:11])[CH3:14]
Reactant: CCOC(=O)C(C)(Sc1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(C(=O)OCC)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of (3S,4S)-4-(1-phenylthio-1-ethoxycarbonylethyl)- 3-(1-(R)-p-nitrobenzyloxycarbonyloxyethyl)-2-azetidinone (2.0 g) in dry dichloromethane (50 ml) was treated with m-chloroperbenzoic acid (0.69 g) for 3 hours while ice-cooling. The reaction mixture was washed successively with a saturated sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue which was dissolved in toluene (18 ml). The toluene solution was stirred under reflux for 1 hour and concentrated in vacuo. An oily residue was purified by silica gel chromatography to yield (3S,4S)-4-(1-ethoxycarbonylethenyl)-3-(1-(R)-p-nitrobenzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>O1CCCC1.CO>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:4](=[S:3])[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:6]=2[CH:12]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)n(C(=O)OC(C)(C)C)c(=S)n2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (60% in oil) (5.55 g; 138 mmol) is added in small portions at 10° C., with stirring, to a solution of 2-mercapto-5-methoxybenzimidazole (10 g; 55.5 mmol) in solution in 400 ml of tetrahydrofuran under argon. The reaction mixture is then stirred for 30 minutes at 0° C., and then BOC2O (26.64 g; 122 mmol) is added in one go. Stirring of the reaction mixture is then carried out for 18 hours at ambient temperature. The reaction mixture is diluted with methanol, filtered over Celite and then concentrated to dryness. The residue obtained is subsequently taken up in a 1/1 mixture of petroleum ether/isopropyl ether. The solid which precipitates is then suction-filtered off to yield the title product in the form of a white powder.
Reaction SMILES: [C:1]1(=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1.CC1C=C(COC2C=C(CCC(O)=O)C=CC=2)C=CC=1C1C=CC=C(OC)C=1>>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:1]2([CH:7]3[C:12](=[O:13])[O:11][C:10]([CH3:14])([CH3:15])[O:9][C:8]3=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)C(=C2CCCCC2)C(=O)O1
Reactant: COc1cccc([Mg]Br)c1
Agent: COc1cccc(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2C)c1
Product: COc1cccc(C2(C3C(=O)OC(C)(C)OC3=O)CCCCC2)c1

Procedure:
5-(2-(3-Methoxyphenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (105.B) was prepared from 105.A and (3-methoxyphenyl)magnesium bromide (1.0 M in THF solution from Aldrich) using a procedure described in Huang, X.; et. al.; Tetrahedron Letters; 1982, (1); pp. 75-76. MS ESI (neg.) m/e: 331.1 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](/[CH:11]=[C:12](/[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)\[C:13]#[N:14])=[CH:4][C:3]=1[O:25]C.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>ClCCCl>[OH:25][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](/[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)\[C:13]#[N:14])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(/C=C(\C#N)c2ccc(C(F)(F)F)nc2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: N#C/C(=C\c1cc(O)c(O)c([N+](=O)[O-])c1)c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (Z)-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile (0.526 g, 1.44 mmol) in 1,2-dichloroethane (10 mL) cooled in an ice-water bath was added aluminium chloride (0.24 g, 1.80 mmol) in one portion followed by pyridine (0.46 g, 5.77 mmol) dropwise. The resulting red suspension was stirred at 80° C. for two hours, then cooled to room temperature and poured onto cold 2 N aqueous hydrochloric acid (100 mL). The precipitate was filtered off, washed with water and dried to give (Z)-3-(3,4-dihydroxy-5-nitrophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile, 0.308 g (61%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
3-Bromo-4-fluorobenzonitrile (0.5 g, 2.4 mmol) was added to a suspension of phenol (0.23 g, 2.4 mmol) and potassium carbonate (0.67 g, 4.8 mmol) in DMSO (2 mL) and the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (3×30 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo to afford the title compound (0.59 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[F:9][CH:10]([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.CN(C)C=O.C(N(CC)CC)C>[Cu]I.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>[F:9][CH:10]([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(C#Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
Into a mixture of ethynylbenzene (1.9 g, 18.5 mmol), 1-(difluoromethoxy)-4-iodobenzene (5 g, 18.5 mmol), N,N-dimethylformamide (35 mL), and triethylamine (12.8 mL, 92.6 mmol) was introduced anhydrous argon for 5 minutes. Then, copper(I) iodide (1.85 mmol, 351 mg) and dichlorobis(triphenylphosphine)palladium(II) (1.11, 0.71 g) were added into the mixture and the new mixture was stirred at 60° C. for 3 hours. The mixture cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification on silica gel (ISCO) using hexanes/EtOAc (100/1) as the eluting solvent, gave 1-(difluoromethoxy)-4-(phenylethynyl)benzene as a clear oil (3.45 g, 76% yield). MS m/e M+ 244; 1H NMR (400 MHz, DMSO-d6) 7.2 (d, J=8.78 Hz, 2H), 7.28-7.45 (m, 4H), 7.5-7.55 (m, 2H), 7.6 (d, J=7.78 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[NH2:29][CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:29][CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1)=[O:27]
Reactant: NC1CCc2ccccc21
Reactant: O=C(Br)CBr
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OC)c(OC)c1
Product: COc1ccc2c(c1)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][OH:29].[I-].[K+]>C(#N)C.O>[OH:29][CH2:28][CH2:27][N:26]([CH3:25])[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(CCO)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.861 mmol) and potassium carbonate (1286 mg, 9.30 mmol) in acetonitrile (5 ml) was added 2-(methylamino)ethanol (0.447 ml, 5.58 mmol). The resulting mixture was stirred overnight at room temperature under argon. The reaction mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel using ethyl acetate as eluent, followed by 10% (2M NH3 in methanol) in dichloromethane. A large amount of starting material was recovered and resubjected to the reaction conditions, using potassium iodide, and heating overnight at 80° C. followed by workup and repurification.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C@@H:3]([NH:11][C@@H:12]([CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([OH:15])=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.Cl.[NH2:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:44]([C:41]1([NH:40][C:13](=[O:15])[C@@H:12]([NH:11][C@@H:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)[C:2]([F:1])([F:37])[F:38])[CH2:16][S:17][C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:43][CH2:42]1)#[N:45]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2(R)-[2,2,2-trifluoro-1-(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid (21.58 g, 40 mmol; Reference D) and 1-aminocyclopropane-carbonitrile hydrochloride (OmegaChem, 6.16 g, 52 mmol) in DMF (75 mL) at rt was added DIPEA (Aldrich, 21 mL, 120 mmol) followed by solid HATU (ChemPacific, 19.77 g, 52 mmol) in one portion. This dark, homogeneous solution was allowed to stir at rt for 24 h. The reaction mixture was quenched by addition of 10% NaHCO3 (50 mL), followed by water (100 mL) and then extracted with EtOAc and the combined organics were washed with brine. Following drying over anhydrous MgSO4 and concentration in vacuo, the resulting dark oil was chromatographed on silica gel with 3/1 hex/EtOAc elution to afford a diastereomer mixture (ranging from 5.7/1 to 12/1) of N-(1-cyanocyclopropyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionamide and (9.83 g) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][N:21]([C:23]3[CH:28]=[C:27]([C:29](=[O:48])[NH:30][C:31]4[CH:36]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:32]=4[O:46][CH3:47])[CH:26]=[CH:25][C:24]=3[CH3:49])[CH:22]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1.CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][N:21]([C:23]3[CH:28]=[C:27]([C:29](=[O:48])[NH:30][C:31]4[CH:36]=[C:35]([C:37]([CH3:38])([CH3:39])[CH3:40])[CH:34]=[C:33]([NH:41][S:42]([CH3:45])(=[O:43])=[O:44])[C:32]=4[O:46][CH3:47])[CH:26]=[CH:25][C:24]=3[CH3:49])[CH:22]=2)=[O:17])[CH2:9]1
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCN(C(=O)OC(C)(C)C)C4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCNC4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of 336 mg (0.481 mmol) of 3-[({1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazole-4-carbonyl}-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (Example 72) in 5 mL CH2Cl2 was added dropwise 1.2 mL of 4N HCl in dioxane. As a gummy yellow precipitate began to form in the flask, 10 drops of MeOH were added and the solution was stirred overnight. The mixture was partitioned between CH2Cl2 (75 mL) and 50% saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous portion was extracted with CH2Cl2 (2×30 mL). The combined extracts were washed with water (30 mL), brine (30 mL), dried (Na2SO4), filtered and concentrated to afford 190 mg of 1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid (piperidin-3-ylmethyl)-amide as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:18][C:19]3[N:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3 (1.1 g, 4.8 mmol), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 125-4 (1.3 g, 4.6 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (2.0 g, 5.3 mmol) in DMF (15 mL) was added DIEA (2.4 mL, 13.8 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into ethyl acetate, washed with saturated NaHCO3 then brine, dried over Na2SO4. The solvent was removed by rotary evaporation to give tert-butyl 4-(6-(2-(4-(2-methylpyridin-4-yl)phenyl)acetamido)pyridin-3-yl)piperazine-1-carboxylate 125. MS m/z 488.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.55 (s, 1H), 8.56 (d, 1H), 8.03 (s, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.74 (s, 1H), 7.66 (d, 1H), 7.51 (d, 2H), 7.42 (m, 1H), 3.75 (s, 2H), 3.08 (b, 2H), 2.57 (s, 2H), 2.54 (s, 4H), 2.51 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]([CH:10]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=2[NH:13][C:12](=[O:23])[CH2:11]1)=[O:9].CI.[Cl-].[NH4+].N>CCCCCC.C(OCC)C>[CH3:6][O:7][C:8]([CH:10]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=2[N:13]([CH3:1])[C:12](=[O:23])[CH2:11]1)=[O:9]
Reactant: COC(=O)C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)C1CC(=O)N(C)c2cc(Cl)ccc2C1=O
Reaction time: 0.67 h

Procedure:
To the mixture, prepared from the dropwise addition of 131 ml of 1.6 molar n-butyl lithium in hexane to 600 ml of liquid amonia while vigorously stirring under an artificial atmosphere of nitrogen for 40 minutes at -76°, 26.7 g of 8-chloro-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester are added all at once and the solution obtained stirred for 1 hour. Thereupon 14.2 g of methyl iodide are added dropwise and the mixture stirred at -35° for 3 hours. It is conbined with 24 g of ammonium chloride and 600 ml of diethyl ether and the ammonia is allowed to evaporate over night at room temperature. 500 ml of water are added to the mixture, its pH adjusted to 6-7 with 6N hydrochloric acid, the organic phase separated and the aqueous layer extracted with diethyl ether. The combined organic solutions are washed with water, dried, filtered, evaporated and the residue recrystallized from diethyl ether, to yield the 8-chloro-1-methyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester melting at 134°-136°.