Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]([NH2:19])([CH2:17][CH3:18])[CH3:16]>CCCCCC>[CH:15]([NH:19][SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)N
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CCC(C)N[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 92 %

Procedure:
In an argon atmosphere, 5.23 g (22.4 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 30 mL of hexane and after adding 3.30 g (45.1 mmol) of sec-butylamine, the mixture was stirred at room temperature for 14 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 98° C./3.5×102 Pa) to obtain 2-sec-butylamino-1,3-di-tert-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHsBu) as a pale yellow liquid (yielded amount: 5.56 g, yield: 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:8]([CH3:19])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:22])=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:8]([CH3:19])[C:4]=1[C:5]([Cl:22])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)Cl
Reaction time: 1.5 h

Procedure:
72 g of 2-methoxy-3-isopropyl-5-sulphamoyl-6-methylbenzoic acid (0.25 mole), 250 ml of chloroform, 23 ml of thionyl chloride and 3 drops of dimethylformamide are placed in a 1 liter flask fitted with an agitator and a condenser. The mixture is heated to reflux for 1.5 hours, then 18 ml of thionyl chloride is added and the reflux is continued for 1.5 hours. The solids dissolve completely.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:16]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[OH:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:16]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NS(=O)(=O)c1cccc(NC(=O)c2nc3ccccc3nc2Cl)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1cccc(NC(=O)c2nc3ccccc3nc2Oc2ccc(F)cc2F)c1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 19.3 %

Procedure:
To a solution of 3-chloro-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (54.4 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) was added 2,4-difluorophenol (19.5 mg, 0.15 mmol) and cesium carbonate (146.6 mg, 0.45 mmol) and the reaction was stirred at 100° C. for 25 minutes. The reaction was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (5) (13.2 mg, 19%). ESI-MS m/z calc. 456.07, found 457.3 (M+1)+; Retention time: 1.76 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.47-8.37 (m, 1H), 8.27-8.15 (m, 1H), 7.97-7.75 (m, 4H), 7.69-7.50 (m, 4H), 7.45 (s, 2H), 7.30-7.17 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH2:15][OH:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>C(O)C.[Pd]>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH2:13][CH2:14][CH2:15][OH:16])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=CCO)cc(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CCCO)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(3,4,5-Trimethoxyphenyl) -2-propen-1-ol (120 mg) was dissolved in ethanol, and to the solution 10% palladium on carbon (60 mg) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, the filtrate was then concentrated under reduced pressure and extracted with chloroform. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=14:1) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=[S:11])=[C:5]([OH:20])[CH:4]=1)#[N:2].N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=[S:11])=[C:5]([O:20][Si:30]([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(NC(=S)Nc2ccccc2Br)c(O)c1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1NC(=S)Nc1ccccc1Br
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of N-(4-cyano-2-hydroxyphenyl)-N′-(2-bromophenyl)thio urea (3.5 g, 10 mmol) in THF (50 mL) at 0° C. was added imidazole (1.0 g, 15 mmol) and TBSCl (1.5 g, 10 mmol). After 1 h, the reaction mixture quenched with water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude material was crystallized from ethyl acetate to give 3.9 g (84%) of N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)thio urea as a yellow solid. 1H NMR (400 MHz, DMSO) δ 9.9 (s, 1H), 9.2 (s, 1H), 8.1 (d, 1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 7.4 (t, 1H), 7.35 (s, 1H), 7.2 (t, 1H); MS(EI) m/e 347 (100 (M+)), 175 (40), 461 (40).
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C>[S:8]([O:11][CH2:7][C@H:2]([C@@H:3]([CH2:4][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:12])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[OH:1])[OH:1])([C:5]1[CH:4]=[CH:3][C:2]([CH3:12])=[CH:7][CH:6]=1)(=[O:9])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](O)COS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
To an ethanol (100 mL) suspension of 1,4 di-O-tosyl-2,3-O-isopropylidene-L-threitol (10.0 g, 21.25 mmol), p-toluenesulfonic acid monohydrate (0.40 g) was added, and the mixture was heated to reflux for 4 days with stirring. The reaction liquor was cooled, and then the solvent was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, to obtain the title compound as a solid. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[CH:19]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:17]=[C:16]3[C:11]=2[N:12]=[CH:13][CH:14]=[N+:15]3[O-])(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:28]=P(Cl)(Cl)Cl>>[CH:1]1([NH:6][S:7]([C:10]2[C:11]3[N:12]=[CH:13][C:14](=[O:28])[NH:15][C:16]=3[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ncc[n+]([O-])c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ncc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(N-cyclopentylsulfamoyl)-7-(3,5-dimethylisoxazol-4-yl)quinoxaline 1-oxide was dissolved in POCl3 and heated to reflux for 1 hour. After cooling to room temperature, volatiles were removed under reduced pressure and dissolved in acetic acid (4 ml). Sodium acetate (100 mg) was added and the solution stirred for 4 hours. Volatiles were removed under reduced pressure and the crude product was purified by preparatory HPLC (5-95% MeCN/H20, 0.1% TFA) to afford the product as a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=2[CH:16]=[C:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[N:11]1([C:14]2[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=2[CH2:16][CH:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=C1NCCC1=Cc1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1NCCC1Cc1ccccc1N1CCNCC1
Temperature: 50 °C
Yield: 81.4 %

Procedure:
A suspension of 3-[2-(4-benzyl-piperazin-1-yl)-benzylidene]-pyrrolidin-2-one (Preparation 15, 6.3 g, 18 mmol) and 10% palladium on carbon (1.5 g) in methanol (100 mL) was placed under a hydrogen atmosphere (50 psi) and was heated at 50° C. for 24 hours. The mixture was filtered through Celite™, fresh 10% palladium on carbon was added (2.0 g), and the mixture was placed under hydrogen (50 psi) and was heated at 60° C. for 7 hours. The mixture was filtered through Celite™, the solvent was removed in vacuo and the residue was purified by silica gel chromatography (20:1 chloroform-methanol w/1% ammonium hydroxide) to give 3.8 g (82% yield) of the title compound. 13C NMR (100 MHz, CDCl3) 180.7, 152.6, 135.5, 130.4, 127.5, 124.5, 120.8, 54.3, 46.8, 42.4, 40.7, 31.9, 27.3; MS (AP/Cl) 260.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (6.00 g) in DMF (50 mL) were added benzyl bromide (6.20 g) and potassium carbonate (5.50 g), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.90 g) as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3ccccc23)CC1
Temperature: 75 °C
Yield: 94.7 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 18 mmol), K2CO3 (5.5 g, 40 mmol), and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 18 mmol), and dimethylforrnamide (6t3 ml) was stirred and heated at 75° C. for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid. Recrystallization (twice) from ethyl alcohol yielded 3.3 g (43%) of 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]bitoxyl]-3-methoxyphenyl]ethanone, m.p.=99°-101° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:20](=[O:21])/[CH:19]=[CH:18]/[CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C(O)/C=C/C1CCOCC1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Product: O=C(/C=C/C1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Following the procedure as described in Example 3, STEP B, the title compound was prepared from 4-bromo-2-nitro-phenylamine (2.06 g, 9.47 mmol) and (E)-3-(tetrahydro-pyran-4-yl)-acrylic acid (prepared as described in PCT Publication WO 2005/101989 (A2,A3), 1.14 g, 7.29 mmol) and was obtained as a yellow solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:17])=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(C2CCCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C2CCCC2)c2ccccc2c1=O

Procedure:
The product of Example 71A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52-11.54 (bs, 1H), 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.97-8.02 (m, 1H), 7.87-7.91 (m, 1H), 7.35-7.47 (m, 4H), 3.62-3.77 (m, 3H), 1.96-2.10 (m, 2H), 1.59-1.87 (m, 6H); MS (ESI) m/z 382 (M+H)+.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[OH:8].[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]([F:23])=[C:14]([CH:22]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[O:8][C:11]1[C:10]([Cl:9])=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[C:13]([F:23])[CH:12]=1
Reactant: O[C@H]1C[C@@H]2CC[C@H]1C2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A mixture of (1S,2S,4R)-bicyclo[2.2.1]heptan-2-ol (1.0 g, 8.92 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (2.88 g, 11.60 mmol), and cesium carbonate (5.81 g, 17.84 mmol) in anhydrous dimethylsulfoxide (12 mL) was heated in a sealed tube at 80° C. for 18 hours, then at 115° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (80 mL), washed with water (30 mL), saturated ammonium chloride (40 mL) and brine (40 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was triturated with methanol to provide the title compound (0.76 g, 25%): 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=7.5 Hz, 1H), 6.57 (d, J=12.4 Hz, 1H), 4.22-4.17 (m, 1H), 2.51-2.46 (m, 1H), 2.38-2.31 (m, 1H), 1.83-1.67 (m, 2H), 1.66-1.58 (m, 1H), 1.56 (s, 9H), 1.52-1.42 (m, 2H), 1.26-1.09 (m, 3H); MS (ES+) m/z 285.0, 287.0 (M-55).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Product: N#Cc1ccc(C(F)(F)F)nc1N1CCCC1
Yield: 67 %

Procedure:
Prepared in 67% yield from 2-chloro-6-trifluoromethyl-nicotinonitrile and pyrrolidine according to the procedure described for Example 178A. MS (ESI+) m/z 242.9 (M+H)+; 1H NMR (DMSO-d6) δ 1.92-1.97 (m, 4H), 3.67-3.72 (m, 4H), 7.07 (d, J=7.8 Hz, 1H), 8.22 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(C(CCCCCCCCCC)C[OH:22])CCCCCCC>>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:22])=[O:5]
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1ccccc1C(=O)O
Reaction time: 0.17 h

Procedure:
Phthalic anhydride (52 g) was added to 2-octyldodecanol (90 g) and the mixture was stirred and heated to 140° for 1 hour and then rapidly to 190° for 10 minutes and then cooled. The mixture was filtered to remove excess phthalic anhydride and any phthalic acid formed, yielding 2-(2'-octyldodecyloxycarbonyl)benzoic acid (110 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=3[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-(4-chlorophenyl)-1-methoxybutan-2-yl)-1H-indol-4-amine (30 mg) and 4-methylmorpholine (46 mg) in DCM (3 mL) was added methanesulfonyl chloride (16 mg) dropwise. Then the mixture was stirred at room temperature overnight. The solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatography on silica gel (20-30% ethyl acetate in hexane) to afford the title compound as a white solid. LC/MS m/z=407.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:30][CH2:31][CH3:32])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)([Cl:42])=[O:41]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:40]([Cl:42])=[O:41])[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:12]=2)=[C:7]([O:30][CH2:31][CH3:32])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazole (19.7 g, 42.144 mmol) and triethylamine (17.6 mL, 126.432 mmol) in methylene chloride (200 mL) cooled to 0° C. was added phosgene (44.6 mL, 84.288 mmol, 20% solution in toluene, Fluka). The reaction mixture was stirred at 0° C. for 30 min then concentrated to dryness. The orange residue was taken in methylene chloride (100 mL), and the solution was filtered through a plug of silica gel (50 g). It was washed with methylene chloride (˜600 mL). The filtrate was concentrated, and the residue was purified by flash chromatography (silica gel, eluting with 10% ethyl acetate in hexane) to give racemic-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride as white solids (12.650 g). The enantiomers of 2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride were separated by chiral chromatography using a Waters Delta Prep 4000 and Modcol spring column (50 mm×70 cm) packed with R,R-Whelk-O1 spherical Kromasil silica gel (purchased from Regis Technologies). Eluent: 30% methylene chloride in hexane. Flowrate: 85 mL/min. Loading scale: 2.4-3.0 g. The first peak coming off the column is the desired (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride.
Reaction SMILES: [Si]([O:8][CH:9]([CH:16]([CH3:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:10][CH:11]=[CH:12][C:13]([O-:15])=[O:14])(C(C)(C)C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:8][CH:9]([CH:16]([CH3:25])[CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][CH:11]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: CC(C=Cc1ccccc1)C(CC=CC(=O)[O-])O[Si](C)(C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C=Cc1ccccc1)C(O)CC=CC(=O)O
Temperature: 23 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
tert-Butyl (2E, 5S, 6R, 7E)-5-[(tert-butyl-dimethylsilyl)-oxy]-6-methyl-8-phenyl-octa-2,7-dienoate (725 mg, 1.74 mmol) was dissolved in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL). The solution was stirred at 23° C. for 4 h then concentrated in-vacuo. Residual trifluoroacetic acid was removed by coevaporation with toluene. Flash chromatography (2% MeOH/CH2Cl2+1% AcOH) afforded the title compound 9 (210 mg, 49%) as pale yellow oil. TLC Rf=0.24 (2% MeOH/CH2Cl2+1% AcOH, KMnO4 stain); 1H NMR (CDCl3, 400 MHz) δ 7.23-7.39 (m, 5H), 7.16 (dt, J=15.6, 7.4, 1H), 6.49 (d, J=15.8, 1H), 6.13 (dd, J=15.8, 8.7, 1H), 5.94 (dt, J=15.6, 1.4, 1H), 3.68 (ddd, J=7.9, 6.0, 3.9, 1H), 2.50-2.56 (m, 1H), 2.36-2.44 (m, 2H), 1.16 (d, J=6.8, 3H); 13C NMR (CDCl3, 101 MHz) δ 171.0, 148.5, 137.0, 132.4, 130.9, 128.8, 127.7, 126.4, 122.9, 73.9, 43.6, 37.5, 17.0; MS (ESI+) m/z 269.1 [M+Na]+ (C15H18NaO3 requires 269.1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([OH:19])[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=CC=CC=2)[CH:10]=1)=[O:8])[CH3:2].[CH3:21]CCCCC.CC(O)C>>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([OH:19])[CH:6]([CH3:21])[C:7](=[O:8])[C:9]1[CH:10]=[CH:11][CH:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](O)CC(=O)c1ccc2ccccc2c1
Reactant: CCCCCC
Solvent: CC(C)O
Product: CCOC(=O)[C@@H](O)C(C)C(=O)c1ccccc1

Procedure:
1H NMR syn (CDCl3) δ=1.26 (t, 3H, J=7.0 Hz), 1.29 (d, 3H, J=7.0 Hz), 3.28 (br, (1H), 3.93 (dq, 1H, J=4.2, 7.0 Hz), 4.25 (q, 2H, J=7.0 Hz), 4.58 (d, 1H, J=4.2 Hz), 7.40-7.65 (m, 3H), 7.90-8.05 (m, 2H); anti (CDCl3) δ=1.20 (t, 3H, J=7.1 Hz), 1.36 (d, 3H, J=7.3 Hz), 3.61 (d, 1H, J=8.3 Hz), 3.98 (dq, 1H, J=4.6, 7.1 Hz), 4.10-4.25 (m, 2H), 4.39 (dd, 1H, J=4.6, 8.3 Hz), 7.40-7.65 (m, 3H); 13C NMR syn (CDCl3) δ=12.1, 14.0, 44.3, 61.9. 71.6, 128.4, 128.7, 133.3, 135.7, 173.1, 201.6; anti (CDCl3) δ=14.0, 14.1, 44.0, 61.5, 73.1, 128.3, 128.7, 133.4, 135.9, 173.1; IR (neat) syn 3480, 3063, 2978, 2936, 1734, 1678, 1596, 1579, 1449, 1369, 1217, 1133, 1062, 1023, 1001, 975, 952, 862, 794, 708; anti 3481, 3059, 2981, 2941, 1738, 1685, 1588, 1454, 1372, 1255, 1209, 1144, 1092, 1024, 973, 701 cm−1; HRMS (FAB); Exact mass calcd for C13H17O4 [M+H]+, 237.1127. Found 237.1118.; HPLC, Daicel Chiralcel AS+ADH+AD, hexane/iPrOH=4/1, flow rate=0.5 mL/min: tR=46.7 min (2S, 3S), tR=50.6 min (2R, 3R), tR=54.3 min (2S, 3R), tR=61.9 min (2R, 3S).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc(N2CCNCC2)c([N+](=O)[O-])c1
Yield: 32.2 %

Procedure:
In n-butanol (20 ml), 1 g of 2-chloro-3,5-dinitropyridine and 2.1 g of anhydrous piperazine were refluxed for 2 hours. Thereafter, n-butanol was distilled off under reduced pressure, followed by extraction with 2N-NaOH and chloroform. The chloroform layer was washed with saturated saline and then dried with anhydrous magnesium sulfate. Under reduced pressure, chloroform was distilled off to obtain 0.4 g of the intended product (yield: 32%).