Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C:22]1(OC)[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3].C(Cl)Cl.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>CC#N>[CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C@H:22]1[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3]
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1C1(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 4 h

Procedure:
To a cooled solution (−15° C.) of (3R,4S,5S,6R)-2-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol in 1:1 CH2Cl2:CH3CN was added triethylsilane followed by addition of BF3.Et2O at a rate such that the temperature was maintained between −15° C. and −10° C. under argon. The reaction mixture was stirred for 4 h prior to being quenched by satd NaHCO3. It was evaporated and the residue was partitioned between EtOAc and water. The organic layer was separated, washed 2× with brine and dried over Na2SO4. Concentration gave a residue, which was purified by preparative TLC (EtOAc:MeOH=20:1, Rf=0.6) to yield 58 mg of title compound as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.46 (s, 1H), 7.35 (s, 1H), 7.04 (s, 4H), 5.92-5.86 (m, 1H), 5.25 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.09 (dd, J=10.4 Hz, 1.6 Hz, 1H), 4.68 (m, 3H), 4.48 (d, J=9.2 Hz, 1H), 4.05-3.86 (m, 4H), 3.83 (dd, J=12.4 Hz, 2.4 Hz, 1H), 3.71-3.62 (m, 2H), 3.50-3.46 (m, 1H), 3.26-3.22 (m, 1H), 2.78-2.74 (m, 1H), 1.13 (d, J=7.2 Hz, 6H); LC-MS (m/z) 463 [(M+1)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1
Reactant: O=C1CCCc2[nH]c3c(Cl)cccc3c21
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccc(F)cc1
Reaction time: 0.37 h
Yield: 70.8 %

Procedure:
8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1973 g, 0.90 mmol) is added to a slurry of pentane-washed NaH (0.0286 g, 0.72 mmol) in DMF (1 mL) and, after stirring for 22 min, p-fluorobenzyl bromide (0.14 mL, 0.0011 mol) is added. Starting material remained after 30 min, so additional NaH (0.0166 g, 0.42 mmol) and DMF (1.8 mL) are added. The mixture is stirred for 1 h, at which time the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from 30% ethyl acetate/hexane and dichloromethane to give 0.2088 g (71%) of the title compound; mp 166-166.5° C.; MS (ESI+) for C19H15ClFNO m/z 328.1 (M+H)+; IR (drift) 1639, 1607, 1510, 1485, 1449, 1426, 1413, 1226, 1189, 1157, 1108, 1095, 830, 790, 734 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.84, 5.78, 6.97, 7.19, 8.27. Anal. Calcd for C19H15ClFNO: C, 69.62; H, 4.61; N, 4.27. Found: C, 69.44; H, 4.55; N, 4.34.
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].ClC1C=C(C)C=CC=1>>[CH2:16]([NH:24][C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCN
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Solvent: O
Solvent: Cc1cccc(Cl)c1
Product: CCCCCCCCNC1=NS(=O)(=O)c2cnccc2N1

Procedure:
A mixture of 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate (0.5 g), octylamine (0.5 mL) and m-chlorotoluene (3 mL) was refluxed for 2-3 h (until completion of the reaction; t.l.c.). Most of the solvents were removed by distillation and the residue was dispersed in a mixture of water (30 mL) and methanol (30 mL) and supplemented with NaOH 10% w/v in water (2 mL). The mixture was treated with charcoal, filtered, and the filtrate was adjusted to pH 6 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried (yield: 0.29 g); m.p. 176°-179° C. (Compound 13).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]2=[CH:5][CH:4]=[C:3]1[C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][CH:11]=3.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:41]([NH:49][C:16]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]2=[CH:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:18])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1ccc2n(c1=O)CCc1ccccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)c1ccc2n(c1=O)CCc1ccccc1-2
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a solution of 4-oxo-6,7-dihydropyrido[2,1,a]isoquinoline-3-carboxylic acid (3-101-03) (76 mg) in DMF (2.0 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric acid salt (EDC, 83 mg), 1-hydroxybenzotriazole (HOBt, 58 mg), and phenethylamine (80 mg) at room temperature. After the reaction mixture was stirred for 18 h, the reaction was quenched with 0.5 mol/L hydrochloric acid. To the reaction mixture was added ethyl acetate and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude crystal was recrystallized to give 4-oxo-6,7-dihydropyrido[2,1,a]isoquinoline-3-carboxylic acid phenethylamide (3-101) (84 mg, 74%) as an yellow crystal.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[NH:6]1[C:10]2=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[CH:7]1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:3][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:6][CH:7]=[CH:8][C:9]=12
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
To a cooled POCl3 (50 mL) in a dried round bottom flask, 1H-pyrrolo[2,3-b]pyridine 7-oxide (5.73 g) was added in potions. The mixture was heated to reflux for 5 h. After cooled down to RT, POCl3 was evaporated under high vacuum under gentle heating (40-50° C.) to obtain black residue. 50 mL of H2O was added slowly and pH was adjusted to 8-9 with Na2CO3 (first with solid, then saturated aqueous solution) The resulting priticipate was collected by filtration, washed with cold H2O and dried in a vacuum oven (50° C.) to give 4-chloro-1H-pyrrolo[2,3-b]pyridine as tan powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][NH:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([N:27]1[CH2:28][C@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C@H:25]([C:29]([OH:31])=[O:30])[CH2:26]1)=[O:36])[CH3:33]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: CCN=C=O
Product: CCNC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)O)C1
Yield: 84.7 %

Procedure:
According to the procedure of Example 17, Step 3, the reaction of 178 mg of cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid (Example 21, Step 1) and 44 mg of ethyl isocyanate provided 175 mg of cis-1-[(ethylamino)carbonyl]-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid in quantitative yield. MS: 513.2 (M+H)+
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[O-:11][C:12]#[N:13].[K+]>O>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:12]([NH2:13])=[O:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)CNC(N)=O
Temperature: 0 °C

Procedure:
To a solution of glycine tert-butyl ester hydrochloride (15.13 g, 89.5 mmol) in water (12 ml), a warm solution of potassium cyanate (8.89 g, 107.4 mmol) in water (12 ml) is added in one portion. The clear solution is heated to 65° C. to 70° C. for 15 minutes before removing from heat and cooling to 0° C. in an ice bath. MeOH (approximately 5 ml) is added to dissolve the oil formed and the mixture allowed to sit at 0° C. The crystals formed are filtered, washed with ice water (3×2 ml) and dried to give the title compound; [M+H]+ 174
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH2:8](Br)[CH2:9][CH3:10].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:8]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])[CH2:9][CH3:10]
Reactant: COC(=O)CN
Reactant: CCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCNCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A suspension of glycine methyl ester HCl (5.0 g, 39.8 mmol) in acetonitrile (100 mL) was treated with propyl bromide (3.7 mL, 39.8 mmol), and diisopropylethylamine (13.9 mL, 79.6 mmol). After stirring at room temperature for 1 hour, the mixture was heated at reflux overnight. Solution occurred at reflux temperature. The solvent was removed under reduced pressure and the residue triturated with Et2O/EtOAc. Filtering and removal of the solvent under pressure left 1.13 g of the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (98:2) gave 0.53 g (10.2% yield) of the product as a yellow oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][SH:24]>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:24][CH2:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: SCc1ccccn1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3ccccn3)c21
Yield: 64.8 %

Procedure:
The title compound (cis/trans=20/80) was prepared as a yellow oil in 64.8% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans-22/78) and 2-pyridylmethanethiol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 50 °C

Procedure:
The 467.3 g of 2-cyano-4'-methylbiphenyl prepared above are dissolved in 4.7l of 1,2-dichloroethane in the presence of 467.3 g of N-bromosuccinimide and 9.3 g of benzoyl peroxide. The mixture is heated very gradually so as to have good control over the exothermic effect. It is subsequently refluxed for 4 h, cooled to 50° C. and then washed 3 times with hot water and dried and the organic phase is concentrated to give cream-colored crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([O:27][CH3:28])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:7]2[OH:26]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:3]([O:27][CH3:28])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)O)=C2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4-hydroxy-1,1-dimethyl-7-methoxyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (92 mg, 234 μmol) in 2 mL TFA was stirred at room temperature for 30 minutes, M+1=338. The mixture was concentrated and then triturated in DCM/hexane (5:10). The solid was filtered, washed with 10 mL DCM/hexane (5:10), and dried under high vacuum to give 72 mg of the product as a pale yellow solid. MS (m/z)=338 (M+H)+. Calculated for C16H16FNO6 337.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=O)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23]>C(O)C.CN1C(=O)N(C)CCC1.C(O)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][N:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: OCCNCCO
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CN1CCCN(C)C1=O
Solvent: CCO
Product: OCCN(CCO)Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1

Procedure:
109 mg (0.40 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage 1.6) and 84 mg (0.8 mmol) of diethanolamine in 6 ml of ethanol, 60 drops of DMPU and 50 μl of acetic acid are stirred at RT for a few hours. 30 mg of Raney nickel are then added and the mixture is hydrogenated at 50° C. The catalyst is filtered off and the filtrate is evaporated. Column chromatography (SiO2, CH2Cl2/methanol=10:1) and crystallization from ethyl acetate/diethyl ether yields 4-(3-chloroanilino)-6-[bis(2-hydroxyethyl)aminomethyl]-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=7.0; TLC-Rf=0.1 (CH2Cl2/methanol=10:1); FAB-MS: (M+H)+=362.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[CH2:3][CH2:2]1.[N:23]([CH3:26])=[C:24]=[O:25]>ClCCCl>[CH3:26][NH:23][C:24]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[CH2:5][CH2:6]1)=[O:25]
Reactant: CN=C=O
Reactant: O=c1[nH]c2nccc(NC3CCNCC3)c2c2ccccc12
Solvent: ClCCCl
Product: CNC(=O)N1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
358 (50 mg, 0.17 mmol) and isocyanatomethane (15 mg, 0.25 mmol) were suspended in DCE (2 mL), and stirred overnight at room temperature. The crude material was purified directly via HPLC to provide 359 (26 mg, 44% yield) as a solid. LC-MS (M+H=351, obsd.=351).
Reaction SMILES: [NH2:1][C@@:2]1([C:12]([OH:14])=[O:13])[CH2:7][C@H:6]([OH:8])[C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10].[C-]#N.[K+].C(Br)C1C=CC=CC=1>CCO.O.CCOC(C)=O>[NH2:1][C@@:2]1([C:12]([OH:14])=[O:13])[CH2:7][C:6](=[O:8])[C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10]
Reactant: N[C@@]1(C(=O)O)C[C@H](O)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: BrCc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 40 °C
Yield: 18.9 %

Procedure:
(1S*,2S*,4S*,5R*,6R*)-Ethyl 2-(3′-benzyl-5′-spirohydantoin)-4-hydroxybicyclo[3.1.0]hexane-6-carboxylate. To a stirred solution of the product of Example 1, step (c) (14.5 g, 78.7 mmol) in EtOH/H2O (2:1) (150 mL total volume) was added NH2CO2NH4 (18.42 g, 236 mmol) then KCN (7.68 g, 118 mmol). Upon complete addition, the reaction mixture was warmed at 40° C. for 2 days. The reaction mixture was concentrated in vacuo, partitioned with EtOAc/1N HCl, and brine. The mixture of hydantoins was extracted with EtOAc, dried over MgSO4, and concentrated. The crude hydantoins were reconstituted in DMF (50 mL) and stirred at room temperature as NaHCO1 (16.85 g, 200 mmol) and then benzyl bromide (12.6 g, 73.5 mmol) were consecutively added. The reaction mixture was warmed at 100° C. overnight. The reaction mixture was diluted with EtOAc and partitioned with 0.5 N HCl. The hydantoins were extracted with EtOAC, washed with H2O then brine, dried over MgSO4, and purified via HPLC (hexanes/EtOAc) to afford 5.14 g (19%, 14.9 mmol) of the title compound. FDMS: M+=344.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4]>[Ru].O1CCOCC1>[CH2:5]([CH:2]1[NH:1][C:3](=[O:4])[CH:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[NH:1][C:3]1=[O:4])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](N)CO
Agent: [Ru]
Solvent: C1COCCO1
Product: CC(C)CC1NC(=O)C(CC(C)C)NC1=O

Procedure:
Refluxing a dioxane solution of (S)-2-amino-4-methylpentan-1-ol with complex 1 (1 mol %) led to 64% isolated yield of the cyclic dipeptide, 3,6-diisobutylpiperazine-2,5-dione 7b after workup (Table 9, entry 1). The product structure was confirmed by MS, NMR spectroscopies.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH2:1]([N:7]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[N:9]=1)[C:14](=[O:16])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCNc1nc(C)no1
Product: CCCCCCN(C(C)=O)c1nc(C)no1

Procedure:
5-n-Hexylamino-3-methyl-1,2,4-oxadiazole (4.6 g, 0.025 mole) was dissolved in acetic anhydride (25 ml) and refluxed for 3 hours and then evaporated down to dryness under vacuum. The residue was taken up in CHCl3 (50 ml) and washed twice with 2 N HCl and twice with a saturated solution of NaHCO3 and dried over MgSO4. (b.p. 113°-114° C./1.0 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20].C(O)C>O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n[nH]1
Yield: 99.1 %

Procedure:
A mixture of ethyl 3-(4-fluorobenzoyl)pyruvate (11.3 g, 47.4 mmol), hydrazine monohydrate (2.50 g, 50.0 mmol) and ethanol (50 mL) was heated under reflux for 1 hr. The reaction mixture was cooled and poured into water. The precipitated solid was collected by filtration, washed with water, and dried to give the title compound (11.0 g, quantitative) as colorless crystals. 1H NMR (CDCl3) δ: 1.41 (3H, t, J=7.2 Hz), 4.41 (2H, q, J=7.2 Hz), 7.05-7.18 (3H, m), 7.76 (2H, dd, J=8.2, 5.4 Hz), 11.21 (1H, s).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15].N[C@H](C(O)=O)CCSC.[OH-].[Na+]>CS(O)(=O)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=[O:15]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: [Na+]
Product: COc1cc2nc[nH]c(=O)c2cc1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 123.3 %

Procedure:
A suspension of 6,7-dimethoxyquinazolin-4(3H)-one (6.18 g), methionine (4.70 g) and methanesulfonic acid (40 mL) was stirred at 130° C. for 3 h, then poured into ice-water. The reaction mixture was adjusted to pH 7 with 40% sodium hydroxide. The mixture was filtered to give the title compound (7.10 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](/[CH:11]=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl-].[CH2:20]1COC[CH2:21]1>>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH:20]=[CH2:21])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)S(=O)/N=C/C1CCC2(CC1)OCCO2
Reactant: C1CCOC1
Agent: [Cl-]
Product: C=CC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution (E)-N-(1,4-dioxaspiro[4.5]decan-8-ylmethylene)-2-methylpropane-2-sulfinamide (1.89 g, 5.53 mmol), prepared in Example 11, step A, in dry THF (48 mL) was treated with a solution of vinylmagnesiumm chloride (10.4 mL, 16.6 mmol, 1.6 N in THF) dropwise at ambient temperature under argon. After the complete addition, the reaction mixture was allowed to stir at room temperature and for 3 hours and then quenched at 0° C. by the cautious addition of saturated ammonium chloride solution. After extraction with ethyl acetate, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-5% MeOH/Ethyl Acetate) to afford the product as a mixture of disatereomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[C:6]([F:17])[C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1.O[CH:20]([C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1)[CH2:21][CH2:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCC=[N+]=[N-])=O)=NC([O-])=O>O1CCCC1>[CH2:31]([O:30][C:28](=[O:29])[C:27]1[CH:33]=[CH:34][C:24]([CH:20]([O:18][C:4]2[CH:5]=[C:6]([F:17])[C:7]([N:8]3[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[N:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:22][CH3:23])=[CH:25][CH:26]=1)[CH3:32]
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Reactant: Oc1cc(F)c(-n2cc(C(F)(F)F)cn2)c(F)c1
Agent: [N-]=[N+]=CCCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Oc1cc(F)c(-n2cc(C(F)(F)F)cn2)c(F)c1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.7 %

Procedure:
3,5-Difluoro-4-(4-trifluoromethyl-pyrazol-1-yl)-phenol (230 mg, 0.871 mmol) was combined with ethyl 4-(1-hydroxybutyl)benzoate (see Intermediate 5) (194 mg, 0.871 mmol) and dissolved in anhydrous tetrahydrofuran (4 mL). Triphenylphosphine (457 mg, 1.74 mmol) was added followed by diazopropyl azodicarboxylate (0.451 mL, 2.18 mmol). This was stirred at room temperature as a yellow solution. At 17 h, the reaction was concentrated. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave impure (+/−)-4-{1-[3,5-difluoro-4-(4-trifluoromethyl-pyrazol-1-yl)-phenoxy]-butyl}-benzoic acid ethyl ester (0.411 g) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 8.06 (d, J=8.2 Hz, 2H) 7.93 (s, 1H) 7.82 (s, 1H) 7.39 (d, J=8.4 Hz, 2H) 6.54 (d, J=9.4 Hz, 2H) 5.15 (dd, J=7.6, 5.3 Hz, 1H) 4.39 (q, J=7.2 Hz, 2H) 1.96-2.10 (m, 1H) 1.77-1.91 (m, 1H) 1.19-1.61 (m, 5H) 0.98 (t, J=7.3 Hz, 3H); MS (M+1): 469.3.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][CH2:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:23]=2)=[CH:15][C:14]=1[C:35]([F:38])([F:37])[F:36]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH:29]3[CH2:34][CH2:33][N:32]([C:2]4[C:3]5[CH2:11][CH2:10][CH2:9][NH:8][C:4]=5[N:5]=[CH:6][N:7]=4)[CH2:31][CH2:30]3)[N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:23]=2)=[CH:15][C:14]=1[C:35]([F:36])([F:37])[F:38]
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: Clc1ncnc2c1CCCN2
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2CCCN3)CC1

Procedure:
The title compound was prepared according to the procedure described for the preparation of A5 by using 4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine coupling with 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine. LC-MS (M+H=518, obsd.=518);