Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.OC1CCNCC1.N1C=CN=CN=1>O>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CSc1nnc(-c2ccc(N(C)C)cc2)c(-c2ccc(N(C)C)cc2)n1
Reactant: OC1CCNCC1
Agent: c1cnncn1
Solvent: O
Product: CN(C)c1ccc(-c2nnc(N3CCC(O)CC3)nc2-c2ccc(N(C)C)cc2)cc1

Procedure:
Three grams of 5,6-bis(4-dimethylaminophenyl)-3-methylthio-1,2,4-triazine and 1.5 g. of 4-hydroxypiperidine were heated at about 150°C. for 12 hours. The reaction mixture was treated with water and the product was collected. The product was dissolved in benzene and the solution was slowly added to n-hexane. The solid which precipitated was recrystallized from ethyl acetate to yield 1.6 g. of 5,6-bis(4-dimethylaminophenyl)-3-(4-hydroxypiperidine-1,2,4-triazine, mp about 186°-188°C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)#N.CC[O:17]CC>>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:17])[CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]C1CCC1
Reactant: CCOCC
Reactant: N#Cc1ccccn1
Product: O=C(c1ccccn1)C1CCC1
Reaction time: 2 h
Yield: 83 %

Procedure:
To an etheral solution of cyclobutyl magnesium bromide (prepared from bromocyclobutane (970 mg, 7.18 mmol) and magnesium (175 mg, 7.18 mmol) in ether (20 ml)) was dropwise added a solution of 2-cyanopyridine (748 mg, 7.18 mmol) in ether (10 ml) at room temperature. After 2 hours, the reaction was quenched by addition of an aqueous saturated solution of NH4Cl. The mixture was extracted with ether. The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel (hexane/AcOEt 95/5) to give the cyclobutyl(2-pyridinyl)methanone 7 as colorless oil (960 mg, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][O:14][CH3:15].C([O-])([O-])=O.[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>CC(C)=O>[CH3:15][O:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc([N+](=O)[O-])cc1
Yield: 104.1 %

Procedure:
A mixture of 40 g of 4-nitrophenol, 41 g of 1-bromo-2-methoxyethane, 45 g of K2CO3 and 80 ml of tris[2-(2-methoxyethoxy)ethyl]amine in 80 ml of acetone is refluxed for 20 hours. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in AcOEt, washed with a 1N solution of NaOH, with water, with a 1N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 59 g of the expected product, which is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.O>CN(C)C=O>[Cl:20][C:19]1[C:14]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:10])([F:9])[F:8])[N:4]=[CH:5]2)=[N:15][CH:16]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:18]=1
Reactant: Cc1[nH]cnc1C(F)(F)F
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
To a solution of 0.50 g (3 m mol) of 5-methyl-4-trifluoromethylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 133 mg (3 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.62 g (3 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 8 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.48 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methyl-4-trifluoromethylimidazole.
Reaction SMILES: C(N(CC)CC)C.[H][H].[CH:10](=[C:17]([CH2:21][OH:22])[C:18]([OH:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.[C].[Pd]>[OH:22][CH2:21][CH:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: [H][H]
Reactant: O=C(O)C(=Cc1ccccc1)CO
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)C(CO)Cc1ccccc1
Yield: 65.7 %

Procedure:
The product (107.8 g) in Reference Example 3, namely 2-benzylidene-3-hydroxypropionic acid, is dissolved in methanol (500 ml), followed by addition of triethylamine (100 ml; 717 mmol) and 5% palladium-carbon (5.00 g; water content of 52.7%) for catalytic reduction in a hydrogen atmosphere for 50 hours. The reaction solution is filtered through Celite to remove the palladium-carbon. The resulting filtrate is subjected to HPLC analysis, indicating that the filtrate contains the title compound (71.0 g; 394 mmol) (at a yield of 65.7% (on a benzaldehyde basis)). The filtrate is concentrated under reduced pressure, and the resulting residue is dissolved in ethyl acetate (600 ml), followed by addition of water (600 ml) and 37% hydrochloric acid (150 ml) and subsequent agitation, to extract the resulting organic phase. The organic phase is washed with an aqueous mixture solution of water (240 ml) and 37% hydrochloric acid and then with saturated saline (300 ml), and dried over anhydrous sodium sulfate. By filtering off the resulting dried matter, the solution is concentrated under reduced pressure, to give a crude product of the title compound. The crude product is dissolved in ethyl acetate (150 ml), followed by addition of hexane (450 ml), and the resulting mixture is gradually cooled from 60° C. to 5° C., to precipitate crystal, which is then filtered and dried to recover the title compound (48.45 g at a purity of 96.5%; 295.5 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[C:16]([OH:18])=O)=[O:4].Cl.CN.C1C=CC2N(O)N=[N:28][C:26]=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:26][NH:28][C:16]([C:6]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][O:9][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:18]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(=O)O
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccccc2)noc1C(=O)OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.3 %

Procedure:
A mixture of 5-(methoxycarbonyl)-3-phenylisoxazole-4-carboxylic acid (50 mg, 0.202 mmol), methylamine hydrochloride (19.12 mg, 0.283 mmol), HOBT (37.2 mg, 0.243 mmol), EDC (46.5 mg, 0.243 mmol) and diisopropylethylamine (0.141 mL, 0.809 mmol) in DMF was stirred at rt for 22 hr. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with saturated potassium bisulfate solution (30 ml), saturated sodium bicarbonate solution (30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to afford methyl 4-(methylcarbamoyl)-3-phenylisoxazole-5-carboxylate (38 mg, 0.146 mmol, 72.2% yield) as a tan solid. HPLC retention time=1.09 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=261.15. 1H NMR (400 MHz, chloroform-d) d ppm 2.97 (d, J=4.77 Hz, 3H) 4.04 (s, 3 H) 7.19 (brs, 1H) 7.42-7.51 (m, 3H) 7.66-7.73 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)C>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.CN1CCCC1=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][N:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CC(O)CCc1cc(Cc2ccccc2)c(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(O)CCc1cc(Cc2ccccc2)c(C#CC2(O)CN3CCC2CC3)cn1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
50 mg of 4-benzyl-5-bromo-2-(3-hydroxybutyl)pyridine, 20 mg of 3-ethynyl-3-quinuclidinol, 20 mg of tetrakis(triphenylphosphine)palladium(0), 5 mg of cuprous iodide and 0.5 ml of triethylamine were added to 2 ml of 1-methyl-2-pyrrolidinone, followed by stirring for one hour in an oil bath kept at 110° C. After cooling as it was, it was evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 5% methanol/ethyl acetate, to give 30 mg of the target compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11](=[O:13])[CH3:12].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH2:10][C:11](=[O:13])[CH3:12])[CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: COc1ccc(I)c(CC(C)=O)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2)c(CC(C)=O)c1
Yield: 112.1 %

Procedure:
A solution of 5.5 g (18.9 mmole) 2-iodo-5-methoxyphenyl-2-propanone (18.9 mmole), 4.15 ml (37.8 mmole) of phenylacetylene, 0.037 g cuprous iodide (1 mole percent) and 0.066 g of bis(triphenylphosphine)palladium (II) chloride (5 mole percent) in 60 ml of triethylamine was stirred for 18 hours under N2 at room temperature. The mixture was partitioned between water and ether. The ether layer was washed successively with cold hydrochloric acid solution, washed and brine. It was dried over MgSO4 and the solvent evaporated in vacuo to give 5.6 g (100% yield) of brown crystals. Recrystallization from methylcyclohexane afforded pure 1-[5-(methoxy)-2-(phenylethynyl)phenyl]-2-propanone, mp 60°-62° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[Li+].CC([N-]C(C)C)C.[I:20]I>C1COCC1.C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([O:10][CH3:11])=[C:2]([F:1])[C:7]=1[I:20]
Reactant: II
Reactant: COc1c(C)cc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C)cc(F)c(I)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1,5-difluoro-2-methoxy-3-methylbenzene (0.65 g, 4.1 mmol) in THF (1 mL) was added to LDA (4.3 mmol) in THF (10 mL) at −55° C. and the solution stirred for 45 minutes. Solid iodine (1.15 g, 4.5 mmol) was added and the solution allowed to warm to ambient temperature. The solution was diluted with ethyl acetate and washed with sodium bicarbonate (saturated solution 15 mL) and sodium thiosulfate (saturated solution, 15 mL), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (hexanes) to give 1,3-difluoro-2-iodo-4-methoxy-5-methylbenzene: 1H NMR (300 MHz, CDCl3): δ 6.72 (dd, 1H), 3.84 (d, 3H,), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=O)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:19].N1CCCCC1>CO>[C:18](/[C:20](=[CH:9]\[C:8]1[CH:11]=[C:12]([O:13][CH3:14])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])/[C:21]([O:23][CH3:24])=[O:22])#[N:19]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCl
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)/C(C#N)=C/c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Yield: 27.1 %

Procedure:
To a mixture of 3.00 g (11.58 mmol) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde and 1.5 mL (16.95 mmol) of methyl cyanoacetate in 30 mL of methanol is added 0.3 mL of piperidine. The mixture is heated at reflux for 5 minutes then cooled slightly and the thick suspension is collected by filtration washing with ethyl acetate followed by diethyl ether to give 1.07 g (27%) of methyl (2E)-2-cyano-3-[4-(2-chloroethoxy)-5-methoxy-2-nitrophenyl]-2-propenoate as a yellow solid, mp softens at 121° C., melts at 157-160° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=S(Cl)[Cl:18].[CH3:20]O>>[ClH:18].[CH3:20][O:14][C:13](=[O:15])[C@@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[NH2:1]
Reactant: O=S(Cl)Cl
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CO
Product: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Product: Cl
Yield: 92.4 %

Procedure:
D-Tryptophan (50.0 kg, 245 mol) was Suspended in MeOH (270 L), then added to a prepared solution of SOCl2 (67.0 kg, 563 mol) in MeOH (250 L) at ambient temperature under a nitrogen (N2) atmosphere. The resulting solution was stirred at reflux for 1 to 2 hours, then MeOH was distilled from the reaction mixture to about 50% of original volume. Methyl t-butyl ether (MTBE) (350 L) was added, and the solution was cooled to 0° to 5° C., with continued stirring for 1 hour. The product was filtered, washed with cold MTBE (150 L), and dried in vacuum at 60° C. to yield 57.6 kg (92.4%) of D-tryptophan methyl ester hydrochloride. 1H NM (400 MHz DMSO) δ: 11.15 (1H, s), 8.70 (2H, exch.), 7.50 (1H, d, J=8.2 Hz), 7.35 (1H, d, J=8.2 Hz), 7.24 (1H, s), 7.08-7.05 (1H, m), 7.00-6.97 (1H, m), 4.18-4.16 (1H, m), 3.61 (3H, s), 3.36-3.25 (2H, m). HPLC Details: Column: SB-Phenyl 4.6×250 mm; Eluent: Isocratic 80% (H2O+0.1% TFA)/20% ACN (acetonitrile); Temperature: 40° C.; Flow Rate=1 mL/min; UV Detection=285 nm; Injection Volume=20 μL; Diluent=1:1 ACN/H2O; and Retention Time=10.0 min.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH2:18]([S:20]Cl)[CH3:19].C(SSCC)C.ClCl>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:20][CH2:18][CH3:19])=[C:7]([OH:11])[CH:6]=1
Reactant: CCSCl
Reactant: N#Cc1ccc(Oc2cccc(O)c2)c(Cl)c1
Agent: ClCl
Solvent: ClCCl
Solvent: CCSSCC
Product: CCSc1ccc(Oc2ccc(C#N)cc2Cl)cc1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2-chloro-4-cyanophenoxy)phenol (0.01 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of ethyl sulfenyl chloride freshly prepared by reacting diethyl disulfide (0.15 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml), with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(2-chloro-4-cyanophenoxy)-2-(ethylthio)phenol as the residue.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CNCCN1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C32H37N6O3Cl2 [(M+H)+] 623.2299, observed 623.2298.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:7]=[C:6]([OH:8])[NH:5][N:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[N:5]1[C:6]([OH:8])=[CH:7][C:3]([C:2]([F:10])([F:9])[F:1])=[N:4]1
Reactant: C1=COCCC1
Reactant: Oc1cc(C(F)(F)F)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cc(C(F)(F)F)nn1C1CCCCO1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
3-(Trifluoromethyl)-1H-pyrazol-5-ol (5.0 g, 0.032 mole) which is known in the art and p-toluene-sulfonic acid monohydrate (0.08 g) were dissolved in ethyl acetate (30 mL) and warmed to 50° C. 3,4-Dihydro-2H-pyran (2.9 g, 0.034 mole) was slowly added over a 10 minute period. After stirring 30 minutes at 50° C., the mixture was cooled and diluted with 100 mL of ethyl acetate. This solution was washed twice with 0.5% hydrochloric acid solution, then dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was treated with 5 mL of ethyl acetate and 20 mL hexanes and filtered to give 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (5.8 g, 76% yield) as a white solid, mp=129°-130° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1NC(C)C1C=CC=CC=1.[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23].C(O)(=[O:29])C>C1COCC1>[OH:25][C:24]1([CH3:26])[CH:4]2[C:3](=[O:29])[C@:2]([CH3:1])([C:11]3[CH:10]=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=3[CH2:5]2)[CH2:23][CH2:22]1
Reactant: CC1=C(NC(C)c2ccccc2)CCc2cc(Cl)ccc21
Reactant: CC(=O)O
Reactant: C=CC(C)=O
Solvent: C1CCOC1
Product: CC1(O)CC[C@]2(C)C(=O)C1Cc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 1-methyl-2-(α-methylbenzylamino)-6-chloro-1,2-didehydrotetralin (79 g; 0.25 mol.) in 500 mL of THF was added methyl vinyl ketone (23 mL; 0.28 mol.). The solution was stirred at ambient temperature, under argon atmosphere, in the dark for 96 hours. Aqueous acetic acid (20%, 500 mL ) was added and the mixture stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated Na2CO3, and dried over Na2SO4. The solvent was removed under vacuum to afford 82 g of the subtitle compound as brown oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[NH:27][C:26]5[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:25]=5[N:24]=4)=[CH:18][CH:17]=3)[C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[NH:27][C:26]5[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:25]=5[N:24]=4)=[CH:18][CH:17]=3)[C:9]([C:11]([OH:13])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(Nc2nc3cc(F)cc(F)c3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncnn2cc(C(=O)O)c(-c3ccc(Nc4nc5cc(F)cc(F)c5[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a mixture of ethyl 4-amino-5-{4-[(5,7-difluoro-1H-benzimidazol-2-yl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (5.85 g, 13.0 mmol) in THF (300 mL) and methanol (100 mL) was added 1N aqueous sodium hydroxide solution (130 mL, 130 mmol). The reaction was stirred at rt overnight and then the solution was concentrated under reduced pressure. The residue was diluted in water (500 mL) and then the mixture was adjusted to pH 3 using concentrated hydrochloric acid. The resulting precipitate was collected by filtration and dried to yield the desired product (5.60 g, 100%) containing some trace impurities. 1H-NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.17-8.38 (br s, 1H) 8.14 (s, 1H), 7.97 (s, 1 H), 7.77 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.93 (dd, J=10.2, 10.2 Hz, 1H) 5.22-5.44 (br s, 1H); ES-MS m/z 422.1 (MH)+; HPLC RT (Method B) 2.13 min.
Reaction SMILES: [Br:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8](C(=O)C2C=CC=CC=2Br)[CH:9]=[C:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]([F:27])([F:26])[F:25])[N:11]=[CH:12]/1)=[O:5].[Li+].[OH-].CCO.CCOC(C)=O>O>[Br:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[N:11][C:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]([F:25])([F:26])[F:27])=[CH:9][N:8]=1)=[O:5]
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cn(C(=O)c2ccccc2Br)/c(=N/C(=O)c2ccccc2Br)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2ccccc2Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Into a 50 mL round bottom flask was placed (E)-2-bromo-N-[1-(2-bromo-benzoyl)-5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-1H-pyrazin-2-ylidene]-benzamide (vi) (50 mg, 0.07 mmol). To this was added LiOH (100 mg), followed by EtOH (25 mL). The resulting solution was allowed to react, with stirring, for 30 minutes while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the resulting solution was diluted with 15 mL of H2O and extracted two times with 10 mL of EtOAc. The organic layers were combined and dried over Na2SO4. After removal of the solvent and volatile components under vacuum, the residue was purified by eluting through a silica gel column with a 1:6 EtOAc/PE solvent system. This resulted in 10 mg (27%) of the final product 2-bromo-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)C#N.[CH2:13]([N:15](CC)CC)C.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([NH:26][C:2]2[CH:9]=[CH:8][C:7]([C:13]#[N:15])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: NC1CCCCC1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 3.0 g (16 mmol) 3-chloro-2-nitrobenzonitrile in 50 ml dimethylformamide was added 1.8 g (18 mmol) dry triethylamine and 1.8 g (18 mmol) cyclohexylamine. The reaction mixture was stirred at 80° C. for 1 h. After cooling to 25° C. 100 ml water was added, and the precipitate was filtered off. The crude product was recrystallized (methanol) to give 1.6 g (65%) N-cyclohexyl-4-cyano-2-nitroaniline. M.p. 109.0° C. 1H-NMR (CDCl3): 8.4-6.8 (4H, m), 3.5 (1H, broad s), 2.4-1.0 (10H, m).