Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14]C(=O)C2C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=2)[CH3:13])[CH2:11][O:10]1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1
Reactant: C[C@@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 98.5 %

Procedure:
[(1R )-1-[(2R )-2-(2,4-Difluorophenyl)-2-oxiranyl]ethyl]3,5-dinitrobenzoate (50 g) was dissolved in two liters of methanol and, at room temperature, 255 ml of 1N sodium hydroxide was added dropwise thereinto. The reaction solution was stirred at room temperature for one hour and neutralized with 127 ml of 1N hydrochloric acid. Methanol was distilled off under reduced pressure, then one liter of ethyl acetate and 200 ml of water were added to the residue, and the mixture was extracted with ethyl acetate. The organic extract was washed with 200 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/3) to give 25 g of (1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1.I[C:13]1[S:17][CH:16]=[N:15][C:14]=1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)#[CH:27]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I.C(OCC)C.C(Cl)Cl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]#[C:27][C:13]2[S:17][CH:16]=[N:15][C:14]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:29][CH:30]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncsc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncsc1C#Cc1ccc(F)cc1
Temperature: 50 °C
Yield: 85.7 %

Procedure:
2.93 g (9 mmol) of caesium carbonate are dried in an evacuated Schlenk flask under temperature, and 50 ml of dry tetrahydrofuran, 978 mg (3.00 mmol) of tert-butyl N-(5-iodo-1,3-thiazol-4-yl)carbamate, 396 mg (3.30 mmol) of 1-ethynyl-4-fluorobenzene, 122 mg (0.15 mmol) of Pd(dppf)2Cl2.CH2Cl2 and 57 mg (0.30 mmol) of CuI are subsequently added under nitrogen. The reaction mixture is heated at 50° C. for 6 h, subsequently cooled and filtered through Celite, and the solvent is removed in vacuo. The residue is taken up with ethyl acetate and washed with saturated NaCl solution. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, and the residue is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1/1), giving 820 mg (2.57 mmol, 85%) of tert-butyl N-{5-[2-(4-fluorophenyl)ethynyl]-1,3-thiazol-4-yl}carbamate as yellow solid from diethyl ether;
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:19])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:19])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reaction time: 1 h
Yield: 64 %

Procedure:
100 mg (0.4 mmol) of compound 7-methoxy-2-phenyl-chromen-4-one obtained in Example 2 was dissolved in methylenechloride, and 2.0 molar equivalents of BBr3 was added thereto. The mixture was stirred for 1 hour. Methanol was added to the mixture, and then solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylenechloride/methanol=5/95, v/v) to give the title compound in a yield of 64%.
Reaction SMILES: [NH:1]1[N:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:9][Si:10]([CH3:13])([CH3:12])Cl>C(N(CC)CC)C>[CH3:9][Si:10]([CH3:13])([CH3:12])[O:3][C:2]1[N:1]=[N:8][CH:7]=[C:5]([O:6][Si:10]([CH3:13])([CH3:12])[CH3:9])[N:4]=1
Reactant: O=c1cn[nH]c(=O)[nH]1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1cnnc(O[Si](C)(C)C)n1

Procedure:
In accordance with the invention, it has further been discovered that the silylation of 6-azauracil with trimethylchlorosilane and triethylamine affords an almost quantitative yield of the required 3,5-bis-trimethylsilyloxy-1,2,4-triazine in pure form when the reaction is carried out in the higher-boiling toluene and when a longer reaction period of time is used.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][CH:8]=1)(C)C.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][CH3:28])[C:21](=[O:29])[C:20]2=[O:30].CNC>CO>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][CH3:28])[C:21](=[O:29])[C:20]2([CH2:14][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:6]#[CH:5])[N:12]=1)=[O:15])[OH:30]
Reactant: CC(=O)c1cccc(C#C[Si](C)(C)C)n1
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: CNC
Solvent: CO
Product: C#Cc1cccc(C(=O)CC2(O)C(=O)N(CCC)c3ccc(Cl)cc32)n1
Temperature: 80 °C

Procedure:
To a clean biotage vial equipped with a stir bar was added 1-(6-((trimethylsilyl)ethynyl)pyridin-2-yl)ethanone (0.0255 grams, 0.12 mmol), 5-chloro-1-propylindoline-2,3-dione, (0.015 grams, 0.067 mmol). This was taken up in 0.2 mL of methanol (purchased from Fisher Scientific). Dimethylamine (2.5 μL 40% in water purchased from Fisher Scientific) was then added and the solution heated in a Biotage initiator microwave for ten minutes at 80° C. Once complete, the reaction was concentrated using a Buchi rotoevaporator and purified using a Teledyne ISCO with silica gel (hexane, ethyl acetate gradient). Yield, 40%. 1H-NMR δ 8.06 (dd, 1H), 7.89 (t, 1H), 7.69 (dd, 1H), 7.35 (d, 1H), 7.29 (dd, 1H), 6.80 (d, 1H), 6.02 (s, 1H), 3.88 (d, 1H), 3.62 (m, 3H), 3.25 (s, 1H), 1.71 (m, 2H), (0.97 (t, 3H). calculated mass for C20H17ClN2O3, 368.09. Observed, 369.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH2:13]1)([CH3:10])[CH3:9].C=O.[C:49]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([N:11]([CH3:49])[C@@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[NH:27][C:26]4[C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[C:19]2=[O:36])[C@H:14]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:39])=[O:40])[CH2:13]1)([CH3:10])[CH3:9]
Reactant: [BH3-]C#N
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To a solution of Example 48 (25 mg, 44 μmol) in methanol (1.5 mL) was added a solution of 37% aqueous formaldehyde (14 mL, 178 μmol). The resulting mixture was stirred for 2 h, then sodium cyanoborohydride (5 mg, 67 μmol) was added. After stirring for 3 h, the mixture was treated with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed in vacuo. The residue was purified by preparative TLC (90:10:1 CHCl3/MeOH/NH4OH). After concentrating the material in vacuo, the resulting oil was dissolved in CH3CN/H2O/TFA and lyophilized to give the title compound (10 mg, 33%) as a white solid and mixture of diastereomers: ESI MS m/z 577 [C29H35F3N4O3S+H]+.
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].C(=O)(O)[O-].[Na+].C[O-].[Na+].I.[NH2:28][C:29]([S:32][CH3:33])=[N:30][NH2:31]>C(Cl)(Cl)Cl.O>[NH2:16][C:5](=[N:31][NH:30][C:29](=[NH:28])[S:32][CH3:33])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Reactant: CSC(N)=NN
Agent: C[O-]
Agent: Cl
Agent: I
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSC(=N)NN=C(N)CS(=O)(=O)c1ccccc1
Yield: 52.8 %

Procedure:
A suspension of 211 g (0.80 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 2 l chloroform was treated with 801 ml 1N aqueous sodium hydoxide. 350 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. The resulting oil was dissolved in 450 ml ethanol and the solution was added to a suspension of 44.6 g (0.82 mol) sodiummethylate and 187 g (0.80 mol) methyl aminomethanehydrazonothioate hydroiodide. After 75 minutes at room temperature 4.8 l of a 3/1 water/saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The organic phase was dried with sodiumsulfate and the solvents were evaporated. Recrystallisation from 1.81 ethanol gave 121 g (53%) 1-[[1-amino-2-(phenylsulfonyl)ethylidene]amino]-2-methyl-2-thiopseudourea (or tautomer), MS m/e (%): 287 (M+H+, 100), 270 (28).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[C:9](O)([CH3:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[C:9]([CH3:13])=[CH:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cccc21)C(C)(O)CC#N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCC(C(C)=CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step B (200 mg, 0.449 mmol), TFAA (283 mg, 1.35 mmol), triethylamine (136 mg, 1.35 mmol) and DMAP (165 mg, 1.35 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by PREP-TLC eluting with PE/EA (3/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=450.0 [M+Na]+.
Reaction SMILES: CC(C)=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:32]3[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41])[CH:35]=[CH:36][CH:37]=3)=[C:11]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:31])([F:30])[F:29])=[O:19])[C:12](=[O:16])[O:13]2)=[CH:8][C:7]=1[CH3:43].[OH-].[Na+:45]>CC(C)=O>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:32]3[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:40]([O-:42])=[O:41])[CH:35]=[CH:36][CH:37]=3)=[C:11]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:29])([F:31])[F:30])=[O:19])[C:12](=[O:16])[O:13]2)=[CH:8][C:7]=1[CH3:43].[Na+:45]
Reactant: Cc1cc2c(-c3cccc(/C=C/C(=O)O)c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1cc2c(-c3cccc(/C=C/C(=O)[O-])c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A mixture of (2E)-3-{3-[7-chloro-3-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl}acrylic acid acetone solvate (1.13 g) and acetone (20.5 ml) was heated to 50° C., and 2N NaOH (0.91 ml) was added dropwise thereto with stirring. The mixture was stirred at 50° C. for 2 hours and then at 5° C. for 1 hour, and crystals precipitated were collected by filtration. The crystals were washed successively with cold acetone/water (95/5, 2 ml) and cold acetone (2 ml) to obtain the title compound (0.974 g, yield 91.9%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([Cl:14])[CH:3]=1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([CH:15]2[CH2:17][CH2:16]2)=[O:7])=[C:4]([Cl:14])[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1Cl
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1Cl)C1CC1
Reaction time: 4 h
Yield: 68 %

Procedure:
To a solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (synthesized by the method of Bioorganic & Medicinal Chemistry Letters 2003, 13, 3983, 5.90 g, 21.0 mmol) in tetrahydrofuran (180 mL) was added dropwise a solution of 0.7 mol/L cyclopropylmagnesium bromide in tetrahydrofuran (65.0 mL, 45.5 mmol) at 0° C. The mixture was stirred at the same temperature for 4 hours, and then to the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→93:7) to give (4-bromo-2-chlorophenyl)(cyclopropyl)methanone (3.75 g, 68%) as a pale yellow oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])(O)=[O:2].S([O-])([O-])(=O)=O.[Na+].[Na+].ClC(OCC)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>O.CCOCC.C(N(CC)CC)C>[N:34]([C:1]([CH2:4][CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:2])=[N+:35]=[N-:36]
Reactant: COc1cccc(C2(CCC(=O)O)CCCCC2=O)c1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(C2(CCC(=O)N=[N+]=[N-])CCCCC2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
About 255 g. of 2-(β-carboxyethyl)-2-(m-methoxyphenyl)-cyclohexanone were mixed with 125 g. of triethylamine and about 20 g. of sodium sulfate. A solution of 99 g. of ethyl chloroformate in 3250 ml. of anhydrous ether was added in dropwise fashion, thus converting the carboxyethyl group to an acid anhydride. The reaction mixture was stirred for about 1 hour at about 0° C. at which point 89 g. of sodium azide in 350 ml. of water were added in dropwise fashion. After the addition had been completed, the reaction mixture was stirred for an additional two hours at 0° C. The organic layer was separated. 2-(β-Azidoformylethyl)-2-(m-methoxyphenyl)cyclohexanone formed in the above reaction was isolated as an oil by evaporation of the ether in vacuo. The residual oil was dissolved in 3.5 1. of benzene, and the solution heated at refluxing temperature for about 1.5 hours. The benzene was removed by evaporation in vacuo. By this procedure the azidoformyl group was rearranged under Curtius conditions to yield the corresponding isocyanate. The benzene was removed by evaporation in vacuo. The residual isocyanate was next hydrolyzed to the cyclic imine by heating overnight in a mixture containing 1200 ml. of water, 1200 ml. of glacial acetic acid and 1200 ml. of 12N aqueous hydrochloric acid. The hydrolysis mixture was cooled and then made strongly basic with 50 percent aqueous sodium hydroxide. 3a-(m-Methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindole thus procuced was extracted into ether, and the ether layer separated, washed with water and dried. Evaporation of the ether layer to dryness yielded 153.2 g. of 3a-(m-methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindole, distilling at about 140° C. at 0.07 mm/g. (For comparison, see Langlois et. al., Tetrahedron, 27, 5641 (1971) compound 10 and page 5647, table 4, compound 42).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C1C=CC=CC=1.C[N:23]([C:25]([O:29]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C[C@@H]1CC[C@H](C2C=CC=CC=2)N1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:25]([NH2:23])=[O:29])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C[C@@H]1CC[C@H](c2ccccc2)N1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 10 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of N,N-dimethyl-1-((2S,5R)-5-phenylpyrrolidin-2-yl)methanamine 250 (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM, 0.1% Et3N) to afford 23 mg of biphenyl amide 247. Yield 45%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49].C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([NH:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(=O)CC1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NCCS(C)(=O)=O)CC1
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of 1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-one (64.6 mg, 0.104 mmole, example 209) and 2-aminoethyl methylsulfone hydrochloride (17.9 mg, 0.112 mmole, Array) in dichloromethane (3 mL) were added sodium acetate (21.1 mg, 0.257 mmole) and sodium triacetoxyborohydride (40.1 mg, 0.189 mmole). The mixture was stirred at room temperature overnight before saturated solution of sodium bicarbonate (3 mL) was added. After stirred for 1 h, the mixture was extracted with dichloromethane (2×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, eluting with a gradient of 1% to 10% methanol in dichloromethane) to give the title compound (56.7 mg, 75% yield). HR-MS (ES, m/z) calculated for C37H48Cl2N5O4S [(M+H)+] 728.2799, observed 728.2796.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[CH3:16][N:17]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CN1CCCC1=O
Reactant: CCCCCCCOc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCCCCCOc1ccc(C#N)cc1
Temperature: 100 °C
Yield: 73 %

Procedure:
Prepared using General Procedure 1: A stirred a solution of 1-bromo-4-(heptyloxy)benzene (2.0 g, 7.37 mmol), zinc cyanide (1.73 g, 14.74 mmol) and tetrakis(triphenylphosphine)palladium (76.12 mg, 0.07 mol) in dry NMP (20 mL) was degassed with N2. The reaction was heated to 100° C. for 18 h while stirring under nitrogen. The reaction mixture was cooled and poured into water (100 mL) and DCM (20 mL). The solid material was removed by filtration and the filtrate was extracted with water (3×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 1.15 g (73%) of 4-(heptyloxy)benzonitrile as a light yellow solid. LCMS-ESI (m/z) calculated for C14H19NO: 217.1; found 218.1 [M+H]+, tR=11.14 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 7.64-7.50 (m, 2H), 7.05-6.83 (m, 2H), 3.99 (t, J=6.5 Hz, 2H), 1.89-1.69 (m, 2H), 1.58-1.12 (m, 8H), 0.90 (dd, J=9.1, 4.5 Hz, 3H). 13C NMR (101 MHz CDCl3) δ 162.47, 133.91, 132.78, 132.12, 129.13, 119.31, 115.18, 103.58, 68.41, 31.73, 28.98, 25.89, 22.58, 14.07.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30]>O1CCOCC1.C(OCC)C>[ClH:30].[CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
N-t-butyloxycarbonyl-L-valyl-L-proline benzylester (16.32 g, 40 mmole) was dissolved in 4N hydrochloric acid in dioxane (100 ml) solution, and the solution was stirred for 1 hour at room temperature. The solvent was distilled off and the residue thus obtained was powdered in diethyl ether to give L-valyl-L-proline benzylester hydrochloride (yield 10.31 g, 75.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2Cl)CC1
Yield: 78.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.2 g, 4.13 mmol), N-(tert-butoxycarbonyl)4-aminomethyl piperidine (0.88 g, 4.13 mmol) and triethylamine(0.86mL, 6.20 mmol) were reacted to form the desired product (1.52 g, 79%). LC-MS (m/z) 468.2 (M+).