Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].O>CCOCC>[CH2:14]([CH:6]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: C(=Nc1ccncc1)c1cccs1
Solvent: O
Solvent: CCOCC
Product: CCCCC(Nc1ccncc1)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.2 %

Procedure:
To a stirred, cooled (10°-20° C.) solution of 3,77 grams of 4-(2-thenylideneamino)pyridine in 100 milliliters of dry ether, a solution containing 0.025 mole butyl lithium in 50 milliliters of dry ether was added dropwise. The resulting solution was stirred at room temperature for 4 hours, and then diluted with 150 ml dry ether before cautious addition of 50 ml. water. The organic phase was dried (MgSO4) and evaporated to dryness to give 5.24 grams of a brown oil. This brown oil was dissolved in toluene and extracted with 2N hydrochloric acid. The extracts were basified with sodium hydroxide and extracted back into toluene. The resulting solution of the base in toluene was dried (MgSO4) and evaporated to dryness. The resulting oil was crystallised from petrol (100°-120° C.)/toluene affording 2.0 grams of a white solid. This material was dissolved in isopropanol and converted to the hydrochloride salt with ethereal hydrogen chloride and crystallised by addition of ether, yielding 1.153 grams of N-[α-butyl-2-thenyl]-4-pyridinamine hydrochloride of melting point 146.5°-148° C.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][O:68][C:69]1[CH:74]=[CH:73][C:72]([CH:75]=O)=[CH:71][CH:70]=1>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:75]([C:72]3[CH:73]=[CH:74][C:69]([O:68][CH3:67])=[CH:70][CH:71]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cncnc5)CC4)c(Cl)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 38.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (19 mg, 0.054 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.16 mmol, 0.16 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.060 mmol, 8 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (9 mg, 38%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.64 (s, 2H, CH2), 3.70 (s, br, 4H, piperazine N(CH2)2), 3.84 (s, 3H, CH3), 7.09 (d, J=8.8 Hz, 2H, methoxyphenyl H-2 & H-6), 8.08 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.12 (d, J=8.8 Hz, 2H, methoxyphenyl H-3 & H-5), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2), 13.32 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[NH2:7])[CH3:3].[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[C:11]#[C:12][CH3:13]>>[CH2:2]([O:4][C:5](=[O:9])[CH:6]([NH:7][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:10][C:11]#[C:12][CH3:13])=[CH:20][CH:19]=1)(=[O:23])=[O:22])[CH3:8])[CH3:3]
Reactant: CCOC(=O)C(C)N
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C)C(=O)OCC)cc1
Yield: 57.6 %

Procedure:
According to the procedure of Example 20, 1.00 g (6.51 mmol) of D,L-alanine ethyl ester hydrochloride reacted with 1.75 g (7.16 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride to provide 1.22 g (58%) of the sulfonamide as a white solid. Electrospray Mass Spec: 325.9 (M+H)+
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12][C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[K+]>ClC=CCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)=[O:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(COc2ccc(SCc3ccc4ccccc4n3)cc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC=CCl
Product: O=C(O)c1ccc(COc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1

Procedure:
4-(4-(2-quinolinylmethylthio)phenoxymethyl)benzoic acid (4 mmol) in dichloroethene (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol) and solid potassium hydrogen carbonate (1.0 g). The reaction is assayed by TLC and upon consumption of the starting thio compound, the mixture is filtered, washed with dilute aqueous sodium bisulfite, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfinyl)-phenoxymethyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[CH:20]=[CH:19]1.C(O)(=[O:27])C>>[O:22]=[C:21]1[CH:20]=[CH:19][C:18](=[O:23])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2([OH:27])[CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Product: CC(C)(c1ccc(N2C(=O)C=CC2=O)cc1)C1(O)C=CC=CC1
Temperature: 25 °C

Procedure:
A 45.46 gram portion of 4-(1-(4-aminophenyl)-1-methylethyl)phenol (0.20 mole) and 500 milliliters of acetic acid were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was maintained at 25° C., then 19.61 grams of maleic anhydride (0.20 mole) dissolved in 100 milliliters of acetic acid was added to the reactor and heating to a reflux commenced. The 126° C. reflux temperature was maintained for 15 hours (54,000 s), then the product was dried under vacuum by rotary evaporation at 100° C. for 60 minutes (3600 s). The crude product was dissolved in 250 milliliters of o-dichlorobenzene at 120° C. and then cooled to 25° C. The light yellow colored solution was decanted away from a brown colored oil layer and dried under vacuum by rotary evaporation at 100° C. for 60 minutes (3600 s) to provide 31.4 grams of 4-(1-(4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)phenyl-1-methyl-ethyl)phenol as a bright yellow colored powder. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][C:5](=[O:18])[C:4]=2[CH:3]=1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: ClCCCCCBr
Reactant: CNC
Product: CN(C)CCCCCOc1ccc2oc(-c3ccccc3)cc(=O)c2c1

Procedure:
The compound was prepared by the method of Example 3 from 6-hydroxyflavone, 1-bromo-5-chloropentane, and dimethylamine: mp 82°-83° C.
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NC2C=CC=CC=2)[N:3]1[CH:25]([C:30]([CH3:32])=[CH2:31])[C:26]([O:28][CH3:29])=[O:27].[ClH:33]>C(Cl)Cl>[Cl:33][C:30]1([CH3:32])[CH:25]([C:26]([O:28][CH3:29])=[O:27])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17][CH2:31]1
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNc1ccccc1
Reactant: Cl
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenylazetidine-1-acetate (0.12 g) was dissolved in dry methylene chloride (5 ml). To this solution was added 5% methanolic hydrochloric acid (0.8 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off and the residue was subjected to column chromatography on silica gel using chloroform as developing solvent to give oily methyl 3-chloro-3 -methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.07 g). Infrared Absorption Spectrum (Chloroform)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[CH3:34])=O>>[CH3:34][C:28]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(C(=O)CBr)c(C)c1
Product: Cc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)c(C)c1
Yield: 47 %

Procedure:
4-[4-(2,4-Dimethyl-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (126 mg, 47%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(2,4-dimethylphenyl)ethan-1-one (available from ASDI Incorporated) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=1.8 Hz, 1H), 8.10-8.18 (m, 2H), 7.85 (s, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.11-7.40 (m, 4H), 2.48 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH:19](O)[CH2:20][O:21][C:22]3[C:27]4[C:28](=[O:37])[CH:29]=[C:30]([C:32]([O:34]CC)=[O:33])[O:31][C:26]=4[CH:25]=[CH:24][CH:23]=3)[C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])C.S(Cl)([Cl:41])=O>ClCCCl>[Cl:41][CH:19]([CH2:20][O:21][C:22]1[C:27]2[C:28](=[O:37])[CH:29]=[C:30]([C:32]([OH:34])=[O:33])[O:31][C:26]=2[CH:25]=[CH:24][CH:23]=1)[CH2:18][O:17][C:13]1[C:9]2[C:10](=[O:12])[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[O:7][C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc4oc(C(=O)OCC)cc(=O)c34)cccc2o1
Solvent: ClCCCl
Product: O=C(O)c1cc(=O)c2c(OCC(Cl)COc3cccc4oc(C(=O)O)cc(=O)c34)cccc2o1

Procedure:
A mixture of 24.5 parts of 5,5'-[(2-hydroxytrimethylene)dioxy]bis [4-oxo-4H-1-benzopyran-2-carboxylic acid] diethyl ester and 47.6 parts of thionyl chloride in 40 parts of dry 1,2-dichloroethane was refluxed for 16 hours. The solvent was then evaporated, the residue was triturated with petrol and the resulting solid was crystallized from ethanol to give 15.6 parts of 5,5'-[(2-chlorotrimethylene)dioxy]bis[4-oxo-4H-1-benzopyran-2-carboxylic acid], diethyl ester as white crystals m.p. 144°-144.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20]N(CCN(C)C)C.[Li]CCCC.CI>>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:20])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)CCN(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CI
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To the solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3 g, 12.6 mmol, 1.0 eq) and TMEDA (3.0 mL, 18.9 mmol, 1.5 eq) THF (120 mL), n-BuLi (7.5 L, 18.9 mmol, 1.5 eq) was added at −78° C. After 3 min, CH3I (3.7 mL, 59.2 mmol, 4.7 eq) was added. After 3 h, the reaction mixture was warmed to RT over 1 h. The reaction was quenched by addition of sat NH4Cl (10 mL) at −78° C. EtOAc (200 mL) and water (100 mL) was added. The organic layer was separated, dried and concentrated to afford 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90% in yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:4][CH:3]=1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:7][CH:6]=3)[C:9]3[N:10]([N:33]=[CH:34][CH:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCOC(=O)CBr
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ccnn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(=O)OCC)cc2)c2ccnn12
Temperature: 70 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a solution of 4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.92 g) in N,N-dimethylformamide (10 mL) were added ethyl bromoacetate (0.66 mL) and cesium carbonate (1.3 g) and the mixture was stirred at 70° C. for 15 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.82 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:36](O)=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:72][NH:73][CH2:74][CH2:75][CH2:76][CH2:77][CH:78]=[CH:79]C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:74]([N:73]([CH3:72])[C:36]([C@@H:9]1[CH2:10][C@H:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=3)[CH:15]=2)[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:37])[CH2:75][CH2:76][CH2:77][CH:78]=[CH2:79]
Reactant: CC=CCCCCNC
Reactant: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Compound 125 (21.33 g) was dissolved in anhydrous DMF (48 mL) at room temperature. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.25 eq.) was added at room temperature and the reaction mixture was stirred for 10 min. Compound 32b (1.1 eq.) was added and the reaction mixture was stirred for additional 10-15 min. After cooling to 5° C., diisopropylethylamine (3 eq.) was added. After warming to room temperature for 1 hr, the reaction mixture was diluted with ethyl acetate, washed with brine and ammonium chloride, dried over Na2SO4, and concentrated under vacuum to give crude 126 (22.09 g) as an orange foam. The crude product was crystallized from ethyl acetate and heptane to give compound 126 (20.8 g) as an off-white powder in 90% yield and 99% purity.
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11].[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[OH:11])[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 55.1 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionic acid methyl ester (262.2 mg, 0.82 mmol) and 2-aminothiazole (165 mg, 1.65 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. %, 2.60 mL, 1.81 mmol) was heated to 100° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and filtered through a pad of celite (ethyl acetate as eluent). The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 ethyl acetate/hexanes) afforded the 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (174 mg, 54.6%) as a white solid: mp 86–88° C.; EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+Na)+ 407.0358, found 407.0361.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1C
Yield: 45.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.032 g (45%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C@H:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@@H:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: c1ccc(C[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 187 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=149-150° C.; 400 MHz 1H NMR (CDCl3) δ: 8.04 (dd, J=7.8, 1.2 Hz, 1H), 7.73 (dd, J=7.8, 0.8 Hz, 1H), 7.64 (td, J=7.6, 1.2 Hz, 1H), 7.48 (td, J=7.4, 1.2 Hz, 1H), 7.34-7.20 (m, 5H), 4.02-3.94 (m, 1H), 2.93 (s, 2H), 2.87 (dd, J=13.3, 6.8 Hz, 2H), 2.78-2.66 (m, 3H), 2.50-2.38 (m, 3H), 2.18-2.08 (m, 2H), 1.94-1.78 (m, 2H); LCMS: 436 [M+H]; enantiomeric excess determined by chiral HPLC: >99%; Chiral HPLC Rt=63.08 min.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([N:42]=[C:43]=[S:44])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:45](Cl)Cl>>[C:34]([NH:42][C:43]([NH:15][CH2:14][CH2:13][CH2:12][C@H:11]([C:16]([NH:18][C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:45])=[CH:23][CH:22]=1)[CH3:20])=[O:17])[NH:10][C:8](=[O:9])[CH:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:44])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(O)cc1
Reactant: ClCCl
Reactant: O=C(N=C=S)c1ccccc1
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=S)NC(=O)c2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of (R)-N2 -(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]ornithine amide (2.0 g; 4.35 mmol; see Example 4(e) above) in CH2Cl2 (50 mL) was added benzoylisothiocyanate (0.59 mL; 4.35 mmol). The reaction mixture was stirred for 24 h at room temperature. The reaction was then concentrated in vacuo and the residue dissolved in EtOAc. The precipitated product, produced by addition of Et2O to the EtOAc solution, was collected and dried to afford 2.25 g (83%) of the sub-title compound as a white solid. The resultant material was used without further characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=[CH:5][CH:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH:59]1[CH2:62][CH2:61][CH2:60]1.C(N(C(C)C)CC)(C)C>CO.C(Cl)Cl>[N:59]1([CH2:21][C:20]2[CH:23]=[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:42]=[CH:43][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[N:10]=3)[C:17]([NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[N:18][CH:19]=2)[CH2:62][CH2:61][CH2:60]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (228 mg, 0.395 mmol) and sodium triacetoxyborohydride (125 mg, 0.592 mmol) were added to a solution of azetidine hydrochloride (Aldrich, St. Louis, Mo.) (48.0 mg, 0.513 mmol) in methanol (2 mL), DCM (2 mL) and diisopropylethylamine (103 μL, 0.592 mmol). The reaction mixture was stirred at ambient temperature for 2 h. More sodium triacetoxyborohydride was added and the mixture was allowed to stir at ambient temperature for 30 min. The reaction mixture was concentrated and diluted with 150 mL of DCM, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, diluted with a small amount of methanol to make the solution clear, dried over sodium sulfate, and concentrated to give 4-(5-(azetidin-1-ylmethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (150 mg, 61.4% yield). m/z (ESI, +ve ion) 619.2 (M+H)+.