Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH2:17][CH3:18])[CH2:15][CH3:16].CS(C1C=C(C=CC=1OC(F)(F)F)C[O:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]([C:39]2[CH:43]=[CH:42][O:41][N:40]=2)[CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=1)(=O)=O.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:15]([C:6]1([CH2:17][CH3:18])[C:5]2[CH:4]=[C:3]([CH2:2][O:27][C:28]3[CH:33]=[CH:32][C:31]([C@@H:34]([C:39]4[CH:43]=[CH:42][O:41][N:40]=4)[CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=3)[CH:12]=[CH:11][C:10]=2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7]1)[CH3:16]
Reactant: CCC1(CC)CCC(C)(C)c2ccc(CBr)cc21
Reactant: CS(=O)(=O)c1cc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)ccc1OC(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(CC)CCC(C)(C)c2ccc(COc3ccc([C@H](CC(=O)O)c4ccon4)cc3)cc21

Procedure:
6-(Bromomethyl)-4,4-diethyl-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (44.2) Starting material 44.1 was prepared according to the published procedure of Kim, C. et al. (Tetrahedron. Lett. 1994, 35 (19), 3017-3020). A mixture of 44.1 (0.5 g, 2.17 mmol), NBS (0.58 g, 3.25 mmol), and dibenzoyl peroxide (53 mg) in CCl4 (10 mL) was heated at reflux for 5 hours. The reaction was cooled, and the precipitate was filtered out. The solvent was removed providing crude 44.2, which was used directly in the next step.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:16])#[N:14].[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[C:13]([C:15]([CH3:16])([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH:25]([OH:26])[C:24]1[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:23]=1[Cl:22])#[N:14]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C#N)n1cncn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C#N)(C(O)c1ccc(Cl)cc1Cl)n1cncn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 3-neck, 250-ml flask equipped with an addition funnel, argon inlet and a septum were added 25 mls of anhydrous tetrahydrofuran and 5.7 mls of diisopropylamine (passed through activity I neutral alumina) under an argon atmosphere. The system was cooled to about 0° C. and 33 mls of 1.6M butyl lithium solution (in hexane) were then added via a syringe. The system was stirred at 0° C. for 5 minutes and then further cooled to -68° C. After cooling, 6.1 gms of 1-cyano-1-(1,2,4-triazol-1-yl)ethane in tetrahydrofuran were added to the system. The system was stirred at -68° C. for 1 hour and then 8.8 gms of 2,4-dichlorobenzaldehyde were slowly added to the system. The system was allowed to warm to room temperature over 30 minutes. Saturated aqueous ammonium chloride was then added to the system and the product was extracted with methylene chloride. The organic solution was washed with water, dried over sodium sulfate and filtered. The solvent was removed by stripping to yield a yellow oil. This oil was then taken up in diethyl ether resulting in the precipitation of 4.1 gms of the erythio isomer of the title compound. The mother liquors were concentrated and again taken up in diethyl ether resulting in the precipitation of 2.60 gms of the threo isomer of the title compound, m.p. 164° -168° C.
Reaction SMILES: C([C:3]1[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)C.Cl.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:24][C:25](Cl)(Cl)Cl>>[CH2:24]([C:11]1([CH:16]=[CH:15][N:14]=[CH:13][CH2:12]1)[C:10]([N:4]1[CH:3]=[CH:7][NH:6][C:5]1=[O:8])=[O:17])[CH3:25]
Reactant: ClCC(Cl)(Cl)Cl
Reactant: O=C(Cl)c1ccncc1
Reactant: CCc1c[nH]c(=O)[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC1(C(=O)n2cc[nH]c2=O)C=CN=CC1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To 3.0 g (27 mmole) of 1,3-dihydro-4-ethyl-2H-imidazole-2-one and 4.74 g (27 mmole) isonicotinoyl chloride hydrochloride in 100 ml tetrachloroethane is added 21.3 g (160 mmole) aluminum chloride. The mixture is stirred at 85° C. for 4 hours and quenched with water. The solution is neutralized with sodium bicarbonate and the suspension filtered. The residue is washed with ethanol and the combined filtrates evaporated to dryness. Chromatography on silica gel afforded the title compound; m.p. 260°-63°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19](O)=[O:20])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:37][C:38]([F:47])([F:48])[C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][CH:44]=1)[CH2:45][NH:46][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][N:24]=[C:16]([C:5]2[CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:17]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinic acid (1 g, 3.06 mmol, 1.00 equiv) in dichloromethane (20 mL), EDC.HCl (970 mg, 5.05 mmol, 1.65 equiv), 4-dimethylaminopyridine (620 mg, 5.08 mmol, 1.66 equiv), and (3-(trifluoromethyl)phenyl)methanamine (590 mg, 3.37 mmol, 1.10 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1˜3:1). This resulted in 800 mg (51%) of N-(3-(trifluoromethyl)benzyl)-2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinamide as a yellow solid.
Reaction SMILES: CSC.B(F)(F)F.CCOCC.[CH3:13][O:14][C:15](=[O:36])[C@@H:16]([O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][C:19]=1[Cl:32]>ClCCl>[CH3:13][O:14][C:15](=[O:36])[C@@H:16]([O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[Cl:32]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1Cl)C(=O)OC
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Solvent: CCOCC
Product: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
Dimethyl sulfide (5.8 ml, 79 mmol) and boron trifluoride diethyl etherate (46% purity, 4.3 ml, 16 mmol) were added to a ice cold solution of (2S)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-propionic acid methyl ester (1.1 g, 3.2 mmol) in dichloromethane (34 ml) under an argon atmosphere. The mixture was stirred for 5 h at ambient temperature, poured into ice water/brine 1/1 and extracted two times with dichloromethane. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a colorless oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to yield 0.6 g (2.3 mmol, 74%) of the title compound as colorless oil.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[CH2:20])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:7])=[O:6].[OH-].[Na+].O.Cl>CO>[CH2:18]([O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([S:5]([NH2:4])(=[O:7])=[O:6])[S:9][C:10]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1ccc2nc(S(=O)(=O)N=CN(C)C)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of product from Step B (0.45 gm, 1.4 mmol) in methanol (1.5 mL) was added to 2N sodium hydroxide (2 mL) and stirred at 40° C. for 1 hour. The reaction was poured into water, acidified (HCl), and the product extracted into ethyl acetate. The extract was dried (Na2SO4) and evaporated to give crude product. Upon trituration of this residue with methylene chloride, the product precipitated and was collected (0.18 gm) and shown to be identical with the product of Example 1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH:22][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.N1C=CC=CC=1.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:21]3[N:22]([CH3:23])[C:34]2=[O:40])[CH2:12]1
Reactant: CNc1nccnc1N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(=O)n([C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)c2nccnc21
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a round bottomed flask was added N2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-N3-methylpyrazine-2,3-diamine (0.1100 g, 0.337 mmol) and pyridine (0.082 mL, Sigma-Aldrich Chemical Company, Inc.) in DCM (1.1 mL) to stir at −40° C. for 30 mins. Triphosgene (0.120 g, 0.404 mmol, Sigma-Aldrich Chemical Company, Inc.) was added to stir for 30 mins. The temperature was brought to 0° C. and allowed to stir for 5 h. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 40% to 100% EtOAc in hexane, to provide the title compound (0.0352 g, 0.100 mmol, 29.6% yield). LCMS showed product peak at 1.51 min (m+1=353.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.72-2.85 (m, 1 H) 2.94-3.08 (m, 1 H) 3.34 (s, 2 H) 4.14-4.28 (m, 1 H) 4.62-4.76 (m, 1 H) 6.98-7.07 (m, 1 H) 7.19-7.26 (m, 1 H) 7.40 (d, J=7.43 Hz, 1 H) 7.64-7.71 (m, 1 H) 7.98 (s, 1 H) 8.52 (d, J=6.65 Hz, 1 H)
Reaction SMILES: CN(C(O[N:9]1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C1(N)C=CC=CC=1N.[CH2:42]([O:49][CH:50]1[CH2:53][CH:52]([C:54](O)=[O:55])[CH2:51]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.O>[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:54]([CH:52]1[CH2:53][CH:50]([O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:51]1)=[O:55]
Reactant: O=C(O)C1CC(OCc2ccccc2)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)C1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
HBTU (2.06 g, 5.44 mmol) was added to a solution of diisopropyl ethylamine (1.03 mL, 5.93 mmol), o-phenylenediamine (0.54 g, 4.95 mmol), and 3-(benzyloxy)cyclobutanecarboxylic acid (1.02 g, 4.95 mmol) in DMF (20 mL) under argon atmosphere at 0° C. The mixture was stirred overnight with gradual warming to RT, then poured into water. The resulting suspension was filtered and the solid was air-dried to give N-(2-aminophenyl)-3-(benzyloxy)cyclobutanecarboxamide (1.17 g, 3.95 mmol, 80% yield) as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20]([OH:22])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:27]1([NH:29][C:20]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH:17]([CH3:19])[CH3:18])=[O:22])[CH2:28][CH2:26]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 164.1 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-isopropyl-1H-1,2,3-triazole-4-carboxylic acid (512 mg, 1.69 mmol) obtained in Example 92a), HOBt (116 mg, 0.847 mmol, 0.5 eq.) and cyclopropylamine (0.157 ml, 2.20 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (398 mg, 2.03 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, the residue was diluted with ethyl acetate-hexane (2:1, 45 ml), and the mixture was washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (3:2, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (476 mg, 1.39 mmol, 91.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]([NH:24][CH3:25])=[O:23])[CH2:6]2.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][Br:30]>>[Br-:30].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N+:19]([CH2:26][C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[CH3:29])=[CH:18][C:17]=1[C:22]([NH:24][CH3:25])=[O:23])[CH2:6]2
Reactant: CNC(=O)c1cnccc1CC1Cc2cc(OC)c(OC)cc2C1=O
Reactant: Cc1ccccc1CBr
Product: CNC(=O)c1c[n+](Cc2ccccc2C)ccc1CC1Cc2cc(OC)c(OC)cc2C1=O
Product: [Br-]

Procedure:
The title compound 143 is prepared according to the procedure reported in Example 38.1 with compound 116 (51.1 mg, 0.15 mmol) and 2-methylbenzyl bromide (40 μL, 0.3 mmol) as reactants. Yellow solid. (Yield 47.5 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH:13](=O)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:13]=1[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=Cc1ccco1
Reactant: Nc1nc[nH]n1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccco2)nc2nc[nH]n12

Procedure:
Compound 1 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0,1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) furfural solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: C(C1C=CC(C(C)C(O)=O)=CC=1)C(C)C.C(NC(=CC1C=CC=CC=1)C(O)=O)(=O)C.S(C1C=CC(CCC[C:44]2[CH:49]=[CH:48][C:47]([P:50]([C:110]3[CH:115]=[CH:114][C:113](CCCC4C=CC(S([O-])(=O)=O)=CC=4)=[CH:112][CH:111]=3)[C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:52]=3[C:61]3[C:70]4[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=4)[CH:64]=[CH:63][C:62]=3[P:71]([C:91]3[CH:96]=[CH:95][C:94](CCCC4C=CC(S([O-])(=O)=O)=CC=4)=[CH:93][CH:92]=3)[C:72]3[CH:77]=[CH:76][C:75](CCCC4C=CC(S([O-])(=O)=O)=CC=4)=[CH:74][CH:73]=3)=[CH:46][CH:45]=2)=CC=1)([O-])(=O)=O>>[CH:113]1[CH:112]=[CH:111][C:110]([P:50]([C:51]2[CH:60]=[CH:59][C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]=2[C:61]2[C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH:64]=[CH:63][C:62]=2[P:71]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:49][CH:48]=2)=[CH:115][CH:114]=1
Reactant: O=S(=O)([O-])c1ccc(CCCc2ccc(P(c3ccc(CCCc4ccc(S(=O)(=O)[O-])cc4)cc3)c3ccc4ccccc4c3-c3c(P(c4ccc(CCCc5ccc(S(=O)(=O)[O-])cc5)cc4)c4ccc(CCCc5ccc(S(=O)(=O)[O-])cc5)cc4)ccc4ccccc34)cc2)cc1
Agent: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Product: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1

Procedure:
According to Example 6, 2-(4-isobutylphenyl) propanoic acid and the methyl ester of acetylaminocinnamic acid were asymmetrically hydrogenated with the Rh- or Ru complexes of (R)-(+)-BINAP-C3 -TS (Table 4).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]1[CH:38]=[N:37][N:36]=[C:35]1[SH:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[CH:20]1[CH2:25][CH2:24][CH:23]([S:39][C:35]2[N:34]([CH3:33])[CH:38]=[N:37][N:36]=2)[CH2:22][CH2:21]1)=[O:4]
Reactant: Cn1cnnc1S
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(Sc2nncn2C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (92 mg, 0.2 mmol, 1.0 eq.), 4-methyl-4H-[1,2,4]triazole-3-thiol (46 mg, 0.4 mmol, 2.0 eq.), triphenylphosphine (105 mg, 0.4 mmol, 2.0 eq.), DIAD (77 μL, 0.4 mmol, 2.0 eq.) and triethyl amine (42 μL, 0.3 mmol, 1.5 eq.) were weighed into a round-bottomed flask containing THF (2.0 mL). The solution was purged with N2 and stirred at room temperature for 12 h. The solution was concentrated to an oil and then purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford 5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (63 mg, 57%).
Reaction SMILES: [CH2:1]1[CH2:7][O:6][CH2:5][CH2:4][NH:3][CH2:2]1.Cl.Cl[C:10]1[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:11]=1[CH:17]=[O:18].CN(P(N(C)C)(N(C)C)=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][N:14]1[C:10]([N:3]2[CH2:2][CH2:1][CH2:7][O:6][CH2:5][CH2:4]2)=[C:11]([CH:17]=[O:18])[C:12]([CH3:16])=[N:13]1
Reactant: C1CNCCOC1
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1nn(C)c(N2CCCOCC2)c1C=O
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Homomorpholine hydrochloride (28.2 g, 200 mol) was added to a mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (21.68 g, 0.1368 mol, Example B(45), Step 2), HMPA (30 mL), water (50 mL), and potassium carbonate (59 g, 0.6 mol) at constant stirring and room temperature. The reaction mixture was heated at 80° C. for 50 h, diluted with water, and extracted with ethyl acetate (3×100 mL). The organic extracts were washed with water to weakly alkaline pH and dried with sodium sulfate. The product was purified chromatographically using hexane/ethyl acetate mixture as eluent to afford the title product (18.7 g, 61%). Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, DMSO-d6): δ 1.91 (m, 2H), 2.27 (s, 3H), 3.33 (m, 4H, overlap with H2O peak), 3.62 (s, 3H), 3.72 (m, 2H), 3.81 (m, 2H), 9.83 (s, 1H). LC/MS (API-ES) calcd for C11H17N3O2: 223.13, found (M+H+): 224.1 m/z.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH2:25][CH2:26][O:27][CH3:28])=[C:10]([C:22](=[O:24])[CH3:23])[C:11]([O:18][CH2:19][O:20][CH3:21])=[CH:12][C:13]=2[O:14][CH2:15][O:16][CH3:17])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[CH2:35]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH2:25][CH2:26][O:27][CH3:28])=[C:10]([C:22](=[O:24])[CH3:23])[C:11]([O:18][CH2:19][O:20][CH3:21])=[CH:12][C:13]=2[O:14][CH2:15][O:16][CH3:17])[CH:5]=[CH:6][CH:7]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: COCCc1c(C(C)=O)c(OCOC)cc(OCOC)c1-c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1c(C(C)=O)c(OCOC)cc(OCOC)c1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
1-[3-(3-hydroxyphenyl)-2-(2-methoxyethyl)-4,6-bis(methoxymethoxy)phenyl]ethanone (25 mg, 0.064 mmol) obtained in Example 134 was dissolved in N,N-dimethylformamide (1.0 mL), and potassium carbonate (35 mg, 0.25 mmol) and benzyl bromide (0.02 mL, 0.17 mmol) were added thereto and stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted twice with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/n-hexane=1/4 to 1/2) to obtain 1-[3-(3-benzyloxyphenyl)-2-(2-methoxyethyl)-4,6-bis(methoxymethoxy)phenyl]ethanone (30 mg, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[C:21]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])[CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][C:62]=1[N:68]1[C:75]2[N:71]([N:72]=[C:73]([C:76]3[CH:77]=[N:78][NH:79][CH:80]=3)[CH:74]=2)[CH:70]=[CH:69]1.N>CN(C=O)C>[CH3:60][C:61]1[CH:67]=[CH:66][C:64]([NH:65][C:17]([C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:22]=[C:21]([S:23]([F:26])([F:28])([F:27])([F:24])[F:25])[CH:20]=2)=[O:19])=[CH:63][C:62]=1[N:68]1[C:75]2[N:71]([N:72]=[C:73]([C:76]3[CH:77]=[N:78][NH:79][CH:80]=3)[CH:74]=2)[CH:70]=[CH:69]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound from Example 16A (320 mg, 0.74 mmol) was dissolved in 2.3 ml of DMF, HATU (309 mg, 0.81 mmol) and then 4-methylmorpholine (0.32 ml) were added, and the mixture was stirred at RT for 30 min. At −5° C., the compound of Example 7A (103 mg, 0.37 mmol) was then added and the mixture was stirred at RT for 16 h. A few milliliters of concentrated aqueous ammonia solution were then added. The mixture was stirred at RT for 15 min and then extracted with ethyl acetate. The organic phase was washed with conc. sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (Method 28). This gave 210 mg (purity 61%, 50% of theory) of the title compound which was used without further purification for the next synthesis step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=Cc1cc(Cl)ccc1OCCCCCBr
Yield: 81.8 %

Procedure:
A mixture of 7.82 g (50 mmol) of 5-chlorosalicylaldehyde, 92.1 g (0.4 mol) of 1,5-dibromopentane, 22.1 g (0.15 mol) of anhydrous granular potassium carbonate, and 360 mL of acetonitrile was stirred and refluxed for 20 hr. The resulting slurry was cooled and diluted with 300 mL of ether. The solids were removed by suction filtration and washed thoroughly with ether. The filtrate and washes were combined and concentrated under water aspirator pressure. The excess 1,5-dibromopentane was removed by distillation under high vacuum. Flash chromatography of the residue on silica gel (eluting with 4:1 hexane-ether) afforded 12.5 g (81.8%) of 2-[(5-bromopentyl)oxy]-5-chlorobenzaldehyde as a yellow oil.