Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:26].[F:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][N:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=[C:41]2[C:49]2([OH:55])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:37][CH:36]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][C:49]([C:41]3[N:40]([CH2:39][C:38]4[CH:56]=[CH:57][C:35]([F:34])=[CH:36][CH:37]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)([OH:55])[CH2:50][CH2:51]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:8]1=[O:26]
Reactant: COc1cc(CN2CCC(CCS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Product: COc1cc(CN2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(4-fluoro-phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[l-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.38 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][C:34]([OH:36])=O.C(N(C(C)C)C(C)C)C.[C:46]([C:50]1[O:54][C:53]([C:55]2[C:56]([NH2:74])=[N:57][CH:58]=[C:59]([C:61]3[N:65]([CH2:66][CH3:67])[N:64]=[C:63]([CH:68]4[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]4)[N:62]=3)[N:60]=2)=[N:52][N:51]=1)([CH3:49])([CH3:48])[CH3:47]>C(#N)C>[NH2:74][C:56]1[N:57]=[CH:58][C:59]([C:61]2[N:65]([CH2:66][CH3:67])[N:64]=[C:63]([CH:68]3[CH2:69][CH2:70][N:71]([C:34](=[O:36])[CH2:33][CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[CH2:72][CH2:73]3)[N:62]=2)=[N:60][C:55]=1[C:53]1[O:54][C:50]([C:46]([CH3:47])([CH3:48])[CH3:49])=[N:51][N:52]=1
Reactant: O=C(O)CCOC1CCCCO1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCn1nc(C2CCN(C(=O)CCOC3CCCCO3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 106 g, 279.51 mmol), was added portionwise to a stirred solution of 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (44.3 g, 254.10 mmol) and N-ethyl-N-isopropylpropan-2-amine (89 mL, 508.21 mmol) dissolved in acetonitrile (600 mL) at 25° C. The resulting solution was stirred at 25° C. for 20 min then 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (101 g, 254.10 mmol) was added portionwise washing the last portion into the mixture as a slurry in acetonitrile (300 mL). After stirring for 1 hour the precipitate was collected by filtration, washing with acetonitrile and drying in vacuo to afford 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one (128 g, 91%) as a beige solid. The filtrate was diluted with DCM (600 ml), washed with water, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of 2 to 2.5% 7N ammonia in methanol with dichloromethane. A second crop of the desired product (40 g, 72.2 mmol, 28.4%) was obtained as a cream solid which was combined with the first crop: 1H NMR Spectrum: (DMSO-d6) 1.29-1.48 (16H, m), 1.48-1.75 (4H, m), 1.83-1.99 (2H, m), 2.48-2.68 (2H, m), 2.68-2.79 (1H, m), 2.87-2.99 (1H, m), 3.07-3.19 (1H, m), 3.32-3.42 (1H, m), 3.47-3.6 (1H, m), 3.64-3.75 (1H, m), 3.75-3.84 (1H, m), 3.84-3.95 (1H, m), 4.24-4.39 (1H, m), 4.47-4.6 (3H, m), 7.84 (2H, s), 8.79 (1H, s): Mass Spectrum [M+Na]+=577.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[CH2:18]([N:22]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]1=[O:28])[CH2:19][CH2:20][CH3:21]>CS(C)=O>[C:13]([C:9]1[CH:10]=[C:11]([CH:24]2[CH:25]([CH:25]3[CH2:24][C:23](=[O:28])[N:22]([CH2:18][CH2:19][CH2:20][CH3:21])[C:26]3=[O:27])[C:26](=[O:27])[N:22]([CH2:18][CH2:19][CH2:20][CH3:21])[C:23]2=[O:28])[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]=1[OH:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCN1C(=O)C=CC1=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCN1C(=O)CC(C2C(=O)N(CCCC)C(=O)C2c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 4 %

Procedure:
This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 (0.1 mol) of 2,6-di-tert-butyl-phenol and 15.31 g (0.1 mol) of N-n-butylmaleimide in dimethyl sulfoxide. The residue is extracted with a 1:1 mixture of hot heptane containing 10 ml of toluene. The heptane extract is concentrated to 150 ml and the resultant solid collected by filtration. The crude product is recrystallized from cyclohexane to give 1.03 g (4%) of a white solid: mp 151°-153° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])=[C:26](Br)[CH:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:37][N:38](C)C=O.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])=[C:26]([C:37]#[N:38])[CH:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CN(C)C=O
Reactant: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(Br)c3)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(C#N)c3)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of this 3-bromo-4-(2'-methylbutyl)benzoic acid 4-octyloxy-4'-biphenylyl ester (5.5 g, 0.01 mol), cuprous cyanide (1.1 g, 0.06 mol) and dimethylformamide (20 ml) was heated to 145°-147° C., following by agitating it for 6 hours, adding a mixture of ferric chloride (4 g), hydrochloric acid (1 ml) and water (7 ml), keeping the mixture at 60°-70° C. for 15 minutes, feeding it into ice water, adding toluene, sufficiently agitating the mixture, transferring it into a separating funnel, several times washing the resulting organic layer with water, drying it over anhydrous MgSO4, distilling off toluene and recrystallizing the residue from ethanol (50 ml) to obtain the objective 3-cyano-4-(2'-methylbutyl)benzoic acid 4'-octyloxy-4-biphenylyl ester (1.7 g). The phase transition points of this product were as follows: ##STR46##
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]2=[CH:4][CH:3]=1.[CH3:13][C:14]([O:16]C(C)=O)=[O:15]>>[C:14]([O:16][CH2:1][C:2]1[N:7]=[C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]2=[CH:4][CH:3]=1)(=[O:15])[CH3:13]
Reactant: Cc1ccc2c([n+]1[O-])OCCO2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccc2c(n1)OCCO2
Yield: 99 %

Procedure:
A solution of 6-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine 5-oxide (60 g, 0.36 mol) in Ac2O (500 mL) was stirred at reflux for 5 hours. The reaction was cooled and the solvent was removed in vacuo to yield (2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)methyl acetate (75 g, 99%) as a dark oil, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[CH:8]([OH:27])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:41](OC(=O)C)([F:43])[F:42]>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:41]([F:43])[F:42])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCC1=C(Cc2ccc(F)cc2)C(O)c2c(OCC(=O)OC)ccc(Cl)c2N1
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of [8-chloro-2-ethyl-3-(4-fluorobenzyl)-4-hydroxy-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.25 g), N,N-dimethylformamide (1.1 mL), potassium carbonate (0.51 g) and acetic acid chlorodifluoromethyl ester (0.33 mL) was stirred at 70° C. for 16 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts dried over sodium sulfate and then the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane gave title compound, 0.06 g.
Reaction SMILES: [C:1](=[S:3])=[O:2].[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]>O.C(O)C>[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:1](=[S:3])[OH:2]
Reactant: NCCCCN
Reactant: O=C=S
Solvent: O
Solvent: CCO
Product: NCCCCNC(O)=S

Procedure:
passing carbonyl sulfide gas into a solution of tetramethylene diamine dissolved in a mixture of water and ethanol in equal proportions by weight at a temperature of from about 30° C. to about 45° C. to form N-(4-aminobutyl)thiocarbamic acid or zwitterion thereof; and
Reaction SMILES: [CH3:1][N:2]1[C:9](=O)[CH:6]2[CH:7]([CH3:8])[CH:5]2[C:3]1=O.COCCO[AlH2-]O[CH2:18][CH2:19]OC.[Na+].[OH-].[Na+].[ClH:25]>C1C=CC=CC=1>[ClH:25].[CH3:1][N:2]1[CH2:9][CH:6]2[C:5]([C:19]3[CH:18]=[CH:7][CH:6]=[CH:5][CH:3]=3)([CH:7]2[CH3:8])[CH2:3]1
Reactant: CC1C2C(=O)N(C)C(=O)C12
Reactant: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC1C2CN(C)CC12c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of N,3-dimethylcyclopropane-1,2-dicarboximide (U.S. Pat. No. 3,166,571, Ex. 2) in benzene is added Vitride® for several minutes. This solution is stirred at ambient temperature for several hours, refluxed for one hour, and then cooled and combined with sodium hydroxide and worked-up and converted to the hydrochloride to give the title product.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[C:5]([OH:7])=[O:6])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(C(=O)O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(C(=O)O)c1cccc(N)c1
Yield: 53.9 %

Procedure:
2-Ethoxy-2-(3-nitrophenyl)acetic acid (6.4 g, 28.4 mmol) was dissolved in absolute ethanol (500 ml), 5% palladium on carbon (wet) (1.5 g) added and the mixture hydrogenated at 60 psi overnight. The suspension was filtered through celite and the filtrate concentrated to give (±)-2-ethoxy-2-(3′-aminophenyl)-acetic acid (3.0 g, 15.3 mmol, 54%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH2:17][CH3:18].[I-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CCOCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2,6-dimethylphenol (20 g) in DMF (10 ml) was added dropwise to a suspension of 60% sodium hydride (4.4 g) in DMF (50 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. To the mixture were added bromoethylethyl ether (12.3 ml) and sodium iodide (16.4 g), and the mixture was stirred at 75° C. overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was distilled under reduced pressure to give 5-bromo-2-(2-ethoxyethoxy)-1,3-dimethylbenzene (24.1 g) as colorless oil.
Reaction SMILES: ClC1C(CO)=C(C(=O)COC)C=NC=1.[Cl:15][C:16]1[C:17]([CH2:29][O:30]C2CCCCO2)=[C:18]([CH2:22][NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:19]=[N:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([CH2:29][OH:30])=[C:18]([CH2:22][NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:19]=[N:20][CH:21]=1
Reactant: CC(C)C(=O)NCc1cncc(Cl)c1COC1CCCCO1
Agent: COCC(=O)c1cncc(Cl)c1CO
Product: CC(C)C(=O)NCc1cncc(Cl)c1CO

Procedure:
Deprotection of the tetrahydropyranyl group in N-[5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-ylmethyl]-isobutyramide according to the synthesis of 1-(5-chloro-4-hydroxymethyl-pyridin-3-yl)-2-methoxy-ethanone yielded the title compound. MS (m/z): 243.0 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[CH3:22])#[N:2].[H-].[Na+].[CH3:25]I>CN(C=O)C>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH3:25])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[CH3:22])#[N:2]
Reactant: CI
Reactant: Cc1cc(C(=O)Nc2ccc(C(F)(F)F)cc2)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4-Cyano-3-methyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.1 (1.10 g, 3.6 mmol) was dissolved in DMF (10 ml) and cooled down to 0° C. Sodium hydride (60% dispersion in oil, 174 mg, 4.3 mmol) was added and the mixture was stirred for 30 min at room temperature. Methyl iodide (0.27 ml, 4.3 mmol) was added and the mixture was stirred for 20 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was re-dissolved in EtOAc, washed with brine, dried and concentrated in vacuo to yield the title compound (1.08 g, 94%).
Reaction SMILES: [N:1]1([C:7]([O:9][CH:10](Cl)[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[C:15]([F:54])=[C:16]([C@@H:20]2[C@:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:23]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:22][C@H:21]2[C:40]([NH:42][C:43]2[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][C:44]=2[O:52][CH3:53])=[O:41])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:1]1([C:7]([O:9][CH:10]([O:49][C:47](=[O:48])[C:46]2[CH:50]=[CH:51][C:43]([NH:42][C:40]([C@H:21]3[C@H:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[C:15]=4[F:54])[C@:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[F:34])([C:25]#[N:26])[C@H:23]([CH2:35][C:36]([CH3:38])([CH3:39])[CH3:37])[NH:22]3)=[O:41])=[C:44]([O:52][CH3:53])[CH:45]=2)[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(Cl)OC(=O)N1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)OC(=O)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 74.2 %

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (2.64 g, 2 mL, 18.5 mmol) was reacted with morpholine (1.69 g, 1.7 mL, 19.4 mmol) and pyridine (1.68 g, 1.72 mL, 21.2 mmol) in methylene chloride (25 mL) at room temperature overnight to give the crude product, 1-chloroethyl morpholine-4-carboxylate. A portion of 1-chloroethyl morpholine-4-carboxylate (670.1 mg, 3.46 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.5 mg, 0.325 mmol) in the presence of cesium carbonate (1.094 g, 3.36 mmol) in dimethylformamide (7 mL) overnight to give, 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl morpholine-4-carboxylate as an off-white solid (186.5 mg, 74% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O7: [(M+H)+]: 773, found: 773
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>>[N+:18]([CH:21]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of methyl 4-formylbenzoate (34 g, 207 mmol) in nitromethane (500 mL) was added ammonium acetate (24 g, 311 mmol) and then the mixture was stirred at 120° C. for 1 h. Evaporated the solvent and diluted with ethyl acetate, the mixture was hydrolyzed and extracted. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain methyl 4-(2-nitrovinyl)benzoate as a yellow solid (26.6 g, yield 62%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.87 (s, 3H), 7.09-8.04 (m, 4H), 8.17-8.21 (d, J=14 Hz, 1H), 8.30-8.34 (d, J=14 Hz, 1H). LC-MS (ESI) m/z: 208 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=1>>[CH3:24][O:23][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([NH:33][C:29]2[CH:28]=[C:27]([O:26][CH3:25])[N:32]=[CH:31][N:30]=2)=[O:16])=[CH:6][CH:5]=1
Reactant: COc1cc(N)ncn1
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Product: COc1cc(NC(=O)N2CCCc3ccc(C(OC)OC)nc32)ncn1

Procedure:
From intermediate 3 and 6-methoxypyrimidin-4-amine, reacted in an analogous manner to the preparation of intermediate 6. (UPLC-MS 1) tR 1.06 min; ESI-MS 360.2 [M+H]+.
Reaction SMILES: CN1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].Cl.[Cl:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:37]=[C:36]([CH2:38][C:39](O)=[O:40])[NH:35][N:34]=3)=[N:27][CH:28]=[N:29]2)=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.O.C(#N)C>[Cl:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:37]=[C:36]([CH2:38][C:39]([NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:9]([F:8])[CH:10]=4)=[O:40])[NH:35][N:34]=3)=[N:27][CH:28]=[N:29]2)=[CH:24][CH:23]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)Cc1cc(Nc2ncnc3cc(OCCCCl)ccc23)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: O=C(Cc1cc(Nc2ncnc3cc(OCCCCl)ccc23)n[nH]1)Nc1cccc(F)c1

Procedure:
4-Dimethylaminopyridine (DMAP), N-methylmorpholine and 3-fluoroaniline (in a large excess) were added to a suspension of (3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic acid.hydrochloride in N,N-dimethylacetamide (DMA) and the resulting slurry was stirred at or below room temperature. A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl) previously dissolved in water was then added in a controlled manner over a period of 8 hour so as to maintain the reaction at ambient temperature. The mixture was seeded with a small amount of product and left to stir for several hours. Anti-solvent acetonitrile followed by water were also added to precipitate more product. The material was isolated by filtration and the cake washed with a mixture of N,N-dimethylacetamide:water:acetonitrile, warm acetonitrile and then dried (in vacuo or under a stream of nitrogen) to yield 2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:32][C:33]1[N:37]([CH3:38])[C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[N:34]=1>COC(O)C(O)OC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH:15]([CH2:32][C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[N:34]=3)[C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cn1c(CCl)nc2ccccc21
Agent: COC(O)C(O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nc4ccccc4n3C)C(=O)O2)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 7.5 %

Procedure:
6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (127 mg, 0.362 mmol) was dissolved in a mixture of dimethoxy ethylene glycol (1.8 ml) and water (1.8 ml). The solution was heated to 80° C. Sodium carbonate (42.2 mg, 0.398 mmol) was then added to the mixture followed by 2-(chloromethyl)-1-methyl-1H-benzimidazole (42.2 mg, 0.398 mmol). The reaction mixture was stirred at 80° C. for 5 hrs, after which time the mixture was acidified to pH 5 and the product was extracted with ethyl acetate (3×25 ml). The combined organics were washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by prep HPLC to afford the title compound as a white solid (13.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.N12CCCN=C1CCCCC2.[CH3:36][CH:37]([CH3:40])[CH2:38][OH:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[O:39][CH2:38][CH:37]([CH3:40])[CH3:36]
Reactant: CC(C)CO
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)COC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 80 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
A mixture of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.0075 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mol) in 2-methylpropanol (25 ml) was stirred for 72 hours at 80° C. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97.5/2.5). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.8 g (25%) of (±)-2-[3-chloro-4-[(4-chloro-phenyl)(2-methylpropoxy)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 133).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:14][CH:13]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOCC>[CH3:20][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[CH:12]1[CH2:14][CH:13]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CC1c1nc(-c2ccccc2)c[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C1CC1c1nc(-c2ccccc2)cn1C
Temperature: 50 °C
Yield: 65.5 %

Procedure:
To a solution of ethyl 2-(4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylate (1025 mg, 4 mmol) in DMF (5 mL) was added potassium carbonate (608 mg, 4.40 mmol) followed by iodomethane (0.275 mL, 4.40 mmol) at rt. The reaction mixture was heated at 50° C. for 12 h. Cooled and diluted with ether (30 mL) and washed with water, brine and dried (Na2SO4). TLC (25% EtOAc in hexane) showed presence of starting material (10-20%). Purified by flash chromatography using 25% EtOAc in hexane to give pure ethyl 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylate (746 mg, 2.62 mmol, 65.5% yield). The ester solidified to a white solid over a period of time. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.79-7.61 (m, 2H), 7.43-7.27 (m, 2H), 7.24-7.14 (m, 1H), 7.02 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.61 (s, 3H), 2.42 (ddd, J=9.0, 6.2, 4.0 Hz, 1H), 2.29 (ddd, J=8.5, 5.3, 4.1 Hz, 1H), 1.69 (ddd, J=8.5, 6.1, 4.0 Hz, 1H), 1.59 (ddd, J=9.1, 5.3, 3.9 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H); MS (ESI) 271 (M+H); Rf=1.90 (Condition A).