Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)C>C(O)C>[N:2]1[NH:5][CH2:7][CH:8]2[CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=12
Reactant: NN
Reactant: CN(C)CC1COc2ccccc2C1=O
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)OCC1CNN=C21
Temperature: 0 °C
Yield: 105.5 %

Procedure:
Hydrazine monohydrate (7.2 g) was dissolved in ethanol (10 ml). Thereto was dropwise added a solution of 3-(N,N-dimethylaminomethyl)-4-chromanone (6.7 g) dissolved in ethanol (10 ml) in a nitrogen atmosphere at room temperature. The resulting mixture was refluxed for 4 hours with heating. The reaction mixture was poured into ice water. Extraction with chloroform was conducted, followed by drying and concentration, to obtain 6 g of a title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:33])[N:14]([N:23]=[CH:24][C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:34]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:33])[N:14]([NH:23][CH2:24][C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: N#Cc1cccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 267A (0.055 g, 0.117 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.234 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.088 mL, 0.176 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.01 (s, 2 H) 6.25 (t, J=6.80 Hz, 1 H) 7.08 (t, J=7.35 Hz, 1 H) 7.28 (m, 2 H) 7.56 (m, 3 H) 7.68 (dd, J=8.09, 2.21 Hz, 2 H) 7.79 (d, J=8.09 Hz, 1 H) 7.86 (d, J=7.72 Hz, 1 H) 7.99 (s, 1 H) 8.09 (dd, J=7.91, 1.29 Hz, 1 H). (ESI−) m/z 470 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11x, and 4-chlorobenzenesulfonyl chloride, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.62 (m, 1H), 8.51 (d, 1H), 7.89 (d, 2H), 7.79 (d, 2H), 7.49 (d, 2H), 7.22 (m, 2H), 7.14 (m, 1H), 7.05 (d, 1H), 6.89 (d, 1H), 6.81 (s, 1H), 4.37 (s, 2H), 4.32 (s, 2H), 3.64 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 536 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:33]2[CH2:38][C@H:37]([CH3:39])[O:36][C@H:35]([CH3:40])[CH2:34]2)=[C:22]([F:32])[C:23]([F:31])=[C:24]([C:26](=[O:30])[C:27]([OH:29])=O)[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1.C(N(CC)CC)C>CN(C=O)C.O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:33]2[CH2:34][C@H:35]([CH3:40])[O:36][C@H:37]([CH3:39])[CH2:38]2)=[C:22]([F:32])[C:23]([F:31])=[C:24]([C:26](=[O:30])[C:27]([N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[O:29])[CH:25]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(=O)O)c(F)c2F)C[C@H](C)O1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(=O)N3CCOCC3)c(F)c2F)C[C@H](C)O1
Yield: 78.5 %

Procedure:
2-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-oxoacetic acid (Intermediate 118, 150 mg, 0.26 mmol), HATU (121 mg, 0.32 mmol), morpholine (0.025 ml, 0.29 mmol) and triethylamine (0.055 ml, 0.40 mmol) in DMF (5 ml) were stirred at room temperature for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layers were washed three times with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate to give the title compound (130 mg, 0.204 mmol, 77%)
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:35])[NH:10][C@@H:11]([CH2:29][C:30]2[N:31]=[CH:32][S:33][CH:34]=2)[C:12]([NH:14][CH2:15][C:16]2[N:17]=[N:18][N:19]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])[CH:20]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:19]1[CH:20]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]2[O:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:35])[CH2:29][C:30]2[N:31]=[CH:32][S:33][CH:34]=2)[N:17]=[N:18]1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2c(F)cccc2F)nn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(NCc1cn(-c2c(F)cccc2F)nn1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 46 (2.4 mg, 0.05 mmol); LiOH (1.1 mg, 0.05 mmol); after extraction afforded the desired product as a while solid (13 mg, 57.3%). 1H NMR (DMSO-d6, 400 MHz): δ 9.00-8.99 (d, 1H, J=1.90 Hz); 8.78-8.76 (t, 1H); 8.60-8.58 (d, 1H, J=8.29 Hz); 8.27 (s, 1H); 7.77-7.69 (m, 1H); 7.49-7.45 (t, 2H); 7.36-7.27 (m, 2H); 4.71-4.65 (m, 1H); 4.44-4.42 (d, 2H, J=5.63 Hz); 3.598-3.593 (d, 1H, J=1.78); 3.360-3.355 (d, 1H, J=1.78); 3.27-3.22 (m, 2H). 13C NMR (DMSO-d6, 100 MHz): 170.69, 169.07, 165.69, 158.07, 158.04, 155.56, 155.53, 154.05, 153.31, 145.67, 136.62, 129.17, 128.48, 126.17, 116.17, 53.23, 52.93, 51.83, 34.67, 33.51. HRMS-ESI: m/z [M+H+] calculated for C19H16F2N6O5S: 479.4343, observed: m/z 479.0960 (M+H+): HPLC Method 2: Rt=17.32 min; 95.9%.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:7]=2[CH2:6]1>C(O)C>[ClH:1].[OH:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:7]=2[CH2:6]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN(CCO)CCC2
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CN(CCO)CCC2
Reaction time: 2 h
Yield: 126.4 %

Procedure:
To a solution of 2-(2-hydroxyethyl)-8-nitro-2,3,4,5-tetrahydro-1H-2-benzazapine hydrochloride (1.51 g, 5.54 mmol) in ethanol (100 ml) was added 10% Pd--C (0.2 g) and the solution was hydrogenated at 50 psi for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give an oil. Evaporation with absolute ethanol gave 2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-2-benzazapin-8-amine hydrochloride as an amorphous solid (1.70 g, 110%) which was used without further purification. A solution of this salt (1.64 g, corrected to 1.50 g, 5.37 mmol) and S-methyl-2-thiophenethiocarboximide hydroiodide (1.91 g, 6.71 mmol) in N-methylpyrrolidinone (8.0 ml) was heated at 45° C. for 6 h. The reaction mixture was poured into water, basified, and extracted with dichloromethane. The dried (magnesium sulfate) organic phase was concentrated to give an oil. Column chromatography on silica gel, using 2% methanol in chloroform saturated with ammonia to 10% methanol in chloroform as eluent, gave a yellow oil (1.69 g, 100%). This oil (1.02 g, 3.23 mmol) was dissolved in ethanol and fumaric acid (0.82 g, 7.91 mmol) was added and the solution was heated at reflux for 0.5 h. Upon cooling, the product was collected to give the monofumarate salt (0.68 g), m.p. 172-4° C.
Reaction SMILES: FC1C=CC=CC=1C1OC2C=CC=CC=2C=1.C1(C2OC3C=CC=CC=3C=2)C=CC=CC=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[O:40][C:41]2[CH:58]=[CH:57][CH:56]=[CH:55][C:42]=2[C:43]=1[S:44]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)(=[O:46])=[O:45].[CH2:59]([N:61]([CH2:66][CH3:67])[CH2:62][CH2:63]CCl)[CH3:60]>>[CH2:59]([N:61]([CH2:66][CH3:67])[CH2:62][CH2:63][CH2:54][O:53][C:50]1[CH:51]=[CH:52][C:47]([S:44]([C:43]2[C:42]3[CH:55]=[CH:56][CH:57]=[CH:58][C:41]=3[O:40][C:39]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[F:32])(=[O:46])=[O:45])=[CH:48][CH:49]=1)[CH3:60]
Reactant: CCN(CC)CCCCl
Reactant: COc1ccc(S(=O)(=O)c2c(-c3ccccc3F)oc3ccccc23)cc1
Agent: Fc1ccccc1-c1cc2ccccc2o1
Agent: c1ccc(-c2cc3ccccc3o2)cc1
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3F)oc3ccccc23)cc1

Procedure:
Substitution of 2-(2-fluorophenyl)benzofuran in the procedure of Example 1 for 2-phenylbenzofuran followed by demethylation of the 2-(2-fluorophenyl)-3-(4-methoxyphenylsulfonyl)benzofuran thus formed and reaction of the resulting product with 3-diethylaminopropyl chloride as described therein gives the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8](B(O)O)[CH:9]=1)([OH:3])=[O:2].Br[C:15]1[C:20]([C:21]#[N:22])=[CH:19][C:18]([C:23]([F:26])([F:25])[F:24])=[N:17][CH:16]=1>>[Cl:13][C:7]1[C:8]([C:15]2[CH:16]=[N:17][C:18]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:20]=2[C:21]#[N:22])=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Cl)c(B(O)O)c1
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Product: N#Cc1cc(C(F)(F)F)ncc1-c1cc(C(=O)O)ccc1Cl

Procedure:
Similarly, 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoic acid was prepared according to the above procedure from 5-carboxy-2-chloro-phenylboronic acid and 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:2][CH:3]1[CH2:8][N:7]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CC1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC1CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
To a flask charged with 2-methyl-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (40 mg, 0.14 mmol) and a stir bar was added 1-(2-bromoethyl)-4-nitrobenzene (65 mg, 0.28 mmol), tetrabutylammonium iodide (5.2 mg, 0.014 mmol), K2CO3 (48 mg, 0.35 mmol), and DMF (2 mL). The mixture was heated to 80° C. for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 399 [M+1]+. (0.14 μM)
Reaction SMILES: C([O:3][P:4]([O:21]CC)([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:5])C.[OH-].[K+]>C(OCC)C.O>[P:4](/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([OH:18])=[O:17])([OH:21])([OH:5])=[O:3]
Reactant: CCOC(=O)CNc1ccccc1C=CP(=O)(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)CNc1ccccc1/C=C/P(=O)(O)O
Yield: 12.3 %

Procedure:
A solution of ethyl N-[2-[2-(diethoxyphosphinyl)ethenyl]phenyl]glycinate (Example 2b)(1.3 g, 3.8 mmol) in diethyl ether (15 ml) is treated with potassium trimethylsilanoate (0.54 g, 4.2 mmol) and stirred over the weekend. The diethyl ether is removed and the oily residue suspended in acetonitrile (50 ml) and stirred under a nitrogen atmosphere for 30 minutes and further treated with trimethylsilylbromide (3 ml) and stirred at room temperature for four hours. 1H-NMR indicates some ester remains so the acetonitrile is removed and the residue is treated with a solution of potassium hydroxide (0.56 g, 10 mmol) in water (3 ml) and stirred for 16 hours. The water is removed and the residue purified on Dowex 50×400 ion exchange resin (water and 2N ammonium hydroxide as eluants). The desired material (fluorescent on tlc under uv light, ninhydrin positive) is obtained from the water eluate as a light, green-white solid (0.12 g).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1.[CH:25](=[O:28])[CH2:26][CH3:27].Cl.C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1.C(O)C>[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[C:21]([CH:25]([OH:28])[CH2:26][CH3:27])[CH:22]=1
Reactant: CCC=O
Reactant: COc1ccc(Cl)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: CCC(O)c1cc(Cl)nnc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
104.6 ml of a 1.6M solution of n-Butyl lithium in hexane is added dropwise at −75° C. to 200 ml tetrahydrofuran followed by 28.3 ml 2,2,6,6-tetramethylpiperidine and the resulting solution is allowed to warm to 0° C. and stirred for 30 min. The solution is cooled to −75° C. and a solution of 11 g 3-chloro-6-methoxypyridazine in 100 ml tetrahydrofuran is added at the same temperature. The reaction is stirred for 30 min at −75° C. A solution of 65.9 ml propionaldehyde in 200 ml tetrahydrofuran is cooled to −75° C. and added to the reaction. The solution is stirred at −75° C. for 90 min, then a mixture of 55 ml concentrated aqueous HCl, 220 ml ethanol and 275 ml tetrahydrofuran is added and the mixture is allowed to warm to room temperature. 150 ml of saturated aqueous sodium bicarbonate is slowly added, and the tetrahydrofuran is removed under reduced pressure. The resulting aqueous phase is extracted 3 times with dichloromethane. The organic phase is dried (MgSO4), filtered and evaporated under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 12.25 g. LC-MS (ES+) 203 (M+H)+. NMR analysis indicated that the product contained approximately 15% of 1-(3-Chloro-6-methoxy-pyridazin-4-yl)-propan-1-ol.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH:15]2[C:23]([NH2:25])=O)=[CH:10][CH:9]=1)[CH3:7]>CN(C=O)C>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH:15]2[C:23]#[N:25])=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCCC1CCC(c2ccc(CC)cc2)C(C(N)=O)C1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC1CCC(c2ccc(CC)cc2)C(C#N)C1
Reaction time: 1 h

Procedure:
65 g of POCl3 are added dropwise with stirring at 50° to a solution of 24 g of 2-(p-ethylphenyl)-5-n-propylcyclohexanecarboxamide in 500 ml of DMF. After further stirring for one hour the reaction mixture is poured onto ice and worked up as customary to give 2-(p-ethylphenyl)-5-n-propylcyclohexanecarbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@H:6]([NH:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]1[N:28](CCC#N)[N:27]=[N:26][N:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@H:6]([NH:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]1[NH:25][N:26]=[N:27][N:28]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of (R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-butyric acid ethyl ester (137 mg, 0.297 mmol) in DCM (8 mL) at room temperature is added DBU (1.507 mL, 10.00 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction is extracted with DCM. The combined organic layer is washed with saturated NH4Cl, brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced. The obtained residue is purified by flash chromatography (silica gel, 2% to 10% EtOH/DCM) to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid ethyl ester (37 mg). To the obtained ester in EtOH (2 mL) at room temperature is added aqueous 1M NaOH (1 mL, 1.0 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction is added 1 mL of aqueous 1M HCl to pH=4, and the mixture is purified by reverse phase HPLC [30% to 60% acetonitrile-H2O (0.1% TFA)] to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid. HPLC retention time=1.24 minutes (condition C); MS (m+1)=380; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (dd, J=6.7, 2.1 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 2.69-2.82 (m, 2H), 3.02 (t, J=7.7 Hz, 2H), 4.17-4.29 (m, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.34 (tt, J=7.3, 1.3 Hz, 1H), 7.42-7.48 (m, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.64 (dd, J=8.2, 1.1 Hz, 2H), 8.00 (d, J=8.1 Hz, 1H), 12.21 (br. s., 1H), 15.92 (br. s., 1H). Chiral HPLC retention time=5.64 min. Column: Daicel CHIRALCEL OJ-H (4.6×100 mm); flow rate=1 ml/min.; eluent: EtOH (containing 0.1% TFA)/heptane=2/8.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CC(C)=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:11])(=[O:12])[NH2:10])=[CH:8][C:4]=2[CH:3]=1)(=[O:24])[CH3:23]
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Reactant: CC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: -5 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A solution of 5-hydroxy-2-sulfamoylbenzo[b]thiophene (4.00 g, 0.017 m) in acetone (70 ml) was cooled to -5° C., triethylamine (1.92 g, 0.019 m) was added, followed by the dropwise addition of a solution of acetyl chloride (1.48 g, 0.019 m) in acetone (10 ml) over 15 minutes, maintaining the temperature at -5° to -3° C. After stirring at -5° C. for 21/4 hours, the mixture was filtered and the solid was washed with acetone. The combined filtrate and washings were concentrated under reduced pressure, the residue was dissolved in ethyl acetate (7.5 ml) washed with water (2×20 ml), dried and evaporated under reduced pressure. The residue was crystallized from 1,2-dichloroethane to yield 4.01 g (87%) of product melting at 129°-132° C. An analytical sample melted at 131.5°-133° C. after recrystallization from 1,2-dichloroethane.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].CO[CH:9](OC)[CH2:10][NH2:11]>C1COCC1>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3]1[NH:11][CH:10]=[CH:9][N:4]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COC(CN)OC
Solvent: C1CCOC1
Product: ClC(Cl)(Cl)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of trichloroacetonitrile (28.8 g, 200 mmol, 1 eq) in anhydrous THF (70 mL) at −60° C. under an argon atmosphere, 2,2-dimethoxyethanamine (21.8 mL, 200 mmol, 1.0 eq) was added dropwise over 5 min. The resulting mixture was allowed to warm to RT and stirred at RT for 4 h. The mixture was concentrated in vacuo and the residue was added in portions to a stirred solution of trifluoroacetic acid (100 mL) at −30° C. under argon. The resulting mixture was then stirred from −30° C. to RT overnight. The reaction mixture was concentrated in vacuo to afford 2-(trichloromethyl)-1H-imidazole. The crude product was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)(C)(C)C.[OH-].[Li+]>O1CCCC1>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C@@H:14]2[CH2:15][CH2:16][CH2:17][C:18]3[C:9]([O:8][CH2:7][C:6]([OH:36])=[O:5])=[CH:10][CH:11]=[CH:12][C:13]2=3)(=[O:21])=[O:22])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(-c2ccccc2Cl)cc1
Yield: 43 %

Procedure:
(R)-[5-(2′-Chloro-biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester was treated with aqueous lithium hydroxide (0.2 M, 1 mL) in tetrahydrofuran (1 mL) overnight, at room temperature. The reaction mixture was concentrated in vacuo. Reverse phase HPLC (Pursuit C-18, 20×150 mm, water/acetonitrile/0.05% trifluoroacetic acid) gave (R)-[5-(2′-chloro-biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid (8.5 mg, 43% over two steps). MS cald. for C24H22ClNO5S 471, obsd. 472 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH2:11].[OH-].[K+]>C(O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([NH:11][CH3:10])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CN
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNc1cc(Cl)nc(N)n1
Yield: 87.9 %

Procedure:
10 g of 2-amino-4,6-dichloropyrimidine are suspended in 100 ml of ethanol. 11.80 g of methylamine are added as a 40% solution in water. The reaction mixture is refluxed for 3 hours. After it has returned to room temperature, 4 g of potassium hydroxide in solution in 40 ml of ethanol are added. After being stirred for half an hour the reaction mixture is filtered on paper. It is evaporated to dryness. The precipitate obtained is taken up in 25 ml of water, filtered off on sintered glass, rinsed with 25 ml of water and then dried in vacuum and over phosphorus pentoxide. 8.50 g of 2-amino-4-methylamino-6-chloropyrimidine are obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH2:51]([O:58][C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][C:62]1([CH3:68])[CH3:67])=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.O>[CH2:51]([O:58][C:59]([N:61]1[CH2:66][CH2:65][N:64]([C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:12])[CH2:63][C:62]1([CH3:68])[CH3:67])=[O:60])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: O=C(O)c1cccc(C2CC2)n1
Reactant: CC1(C)CNCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)c2cccc(C3CC3)n2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
200 mg (1.23 mmol) 6-cyclopropyl-pyridine-2-carboxylic acid was stirred with 450 mg (1.40 mmol) TBTU and 500 μL (2.91 mmol) DIPEA in 5.0 mL DMF at RT. After 10 min, 440 mg (1.23 mmol) 2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester trifluoroacetate was added and the reaction mixture was stirred at RT over night. Water was added and the product was extracted with EtOAc. The organic layers were dried over sodium sulfate and concentrated in vacuo.