Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13]I.[H-].[Na+].C[N:18]([CH3:21])C=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:9])[C:21]#[N:18])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(CC#N)ccc1F
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1cc(C(C)(C)C#N)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
16.67 g (100.93 mmol) of (4-fluoro-3-methoxyphenyl)-acetonitrile is introduced with 30.1 g (211.96 mmol) of methyliodide into 158 ml of dimethylformamide. At 0° C., 8.50 g (211.96 mmol) of a 55-60% sodium hydride suspension is added in portions. After stirring overnight at room temperature, the reaction mixture is poured into ice water and then extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with water and with brine. After the solvent is dried and spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 5.11 g (26.2%) of the desired compound and 6.18 g of the monomethyl compound, which is realkylated, are isolated.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C1C=CN=CC=1)C.CC#N.CCOC(C)=O>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CCNCC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61.2 mg, 0.165 mmol) (see following Steps B, C, D, E, F, G and H for preparation), was added to a solution of diethylamine (0.2 mL, 1.93 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (60 mL), washed with NH4Cl (2×5 mL), NaCl (2×5 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 20.5 mg (30%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.13 (t, J=7.13 Hz, 6 H), 1.46-1.63 (m, 4 H), 1.66 (s, 9 H), 2.25-2.48 (m, 1 H), 3.22-3.29 (m, 4 H), 3.31-3.41 (m, 2 H), 3.94 (m, 2 H), 4.50 (d, J=7.42 Hz, 2 H), 7.89 (dd, J=8.79, 1.76 Hz, 1 H), 7.96-8.04 (m, 1 H), 8.14 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=408.0; Anal. Calcd for C21H33N3O3S+1.00 TFA+0.1H2O+0.30 EtOAc (549.84): C, 52.86; H, 6.71; N, 7.64. Found: C, 52.91; H, 6.52; N, 7.61.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]=O)[CH2:2][CH3:3].C([N:14]1C=CC=C1C=O)(C)C>ClCCl>[CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:14])[CH2:2][CH3:3]
Reactant: CCCn1cccc1C=O
Reactant: CC(C)n1cccc1C=O
Solvent: ClCCl
Product: CCCn1cccc1C#N
Yield: 45 %

Procedure:
In the same manner as described in Reference Example 2 (1) except that 1-n-propylpyrrole-2-carbaldehyde (prepared in the same manner as described in Can. J. Chem., 55, 4112, 1977, b.p. 72°-75°C./5 mmHg) (8.2 g, 60 mmole) is used instead of 1-isopropylpyrrole-2-carbaldehyde and further the product is isolated by silica gel column chromatography (solvent: dichloromethane) instead of distillation under reducted pressure, there is obtained 1-n-propylpyrrole-2-carbonitrile (3.6 g, yield: 45%).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:8][C:9]([F:15])([F:14])S(O)(=O)=O.F[C:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])(F)F>CCCCCC>[F:8][C:9]([F:15])([F:14])[C:1]1[CH:6]=[CH:5][C:4]([C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[CH3:17])=[O:23])=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCCCCC
Product: Cc1ccccc1C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 28 %

Procedure:
In a glass reactor, a mixture of 600 ml of toluene and 22.5 g of trifluoromethanesulfonic acid were kept heated at 110° C., and, while stirring the mixture, 312.8 g of trifluoromethylbenzoyl chloride was dropped into the reactor so as to spend 5 hr in dropping the entire quantity. After that the heating and stirring were continued for 5 hr, and then 1.2 liter of hexane was added to cause precipitation of 4-trifluoromethyl-4'-methylbenzophenone in the form of platy crystals. The cystalline precipitate was collected by filtration, washed and dried. The dried product weighed 276 g (69% yield). From the filtrate, 111 g (28% yield) of 4-trifluoromethyl-2'-methylbenzophenone was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[C@@H:24]([NH2:28])[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39].[Cl-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[C@@H:24]([NH:28][S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCC#Cc1ccc(Cl)cc1
Reactant: CCCS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCC#Cc2ccc(Cl)cc2)c(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of (S)-2-amino-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide and 0.5 ml of triethylamine are dissolved in 50 ml of dioxane. 0.4 ml of 1-propanesulfonyl chloride is added, and the reaction mixture is stirred overnight at room temperature. It is introduced into 200 ml of saturated sodium chloride solution. Extraction is carried out twice using 150 ml of ethyl acetate each time. The organic phases are washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(propylsulfonyl-amino)-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide, which is chromatographed on silica gel with ethyl acetate/n-hexane (1:1) and recrystallised from ethyl acetate/n-hexane, m.p. 131-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C@@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC[N:24](CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C@@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[NH2:24])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: N[C@@H]1CCCC[C@H]1N1CCC(Cc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of (±)-trans-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclohexanol (390 mg, 1.27 mmol) in CH2Cl2 (6 mL) at 0° C. was treated successively with Et3N (350 μL, 2.53 mmol) and MeSO2Cl (194 μL, 2.53 mmol), stirred at 0° C. for 2 hours, and partitioned between CH2Cl2 and 10% NH4OH. The aqueous phase was extracted with CH2Cl2 and the extracts were washed with brine, dried and concentrated. A solution of the residue in THF (3 mL) and 28–30 wt % NH4OH (1.2 mL) was stirred at 70° C. for 24 hours, allowed to cool to room temperature, and partitioned between EtOAc and 1 N NaOH. The aqueous phase was extracted with EtOAc and the extracts were washed with brine, dried and concentrated. Chromatography of the residue on alumina with 1:3 EtOAc:MeOH to 100% MeOH and a subsequent chromatography on alumina with 20:1 hexanes:EtOAc to 100% EtOAc followed by 3:1 EtOAc:MeOH to 100% MeOH gave the product (260 mg, 67%) as a tan oil which solidified upon standing: mp 69.1–70.4° C.; 1H NMR δ 1.03–1.34 (m, 6H), 1.37–1.52 (m, 1H), 1.57–1.77 (m, 5H), 1.92–2.05 (m, 3H), 2.48 (d, J=7.0 Hz, 2H), 2.45–2.64 (m, 3), 2.73 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 307 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17](O)=[O:18]>>[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([OH:12])[CH2:11][CH:2]1[CH3:1])=[O:18]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CC1CC(O)c2ccccc2N1
Product: Cc1ccc(C(=O)N2c3ccccc3C(O)CC2C)cc1C
Yield: 62.5 %

Procedure:
Starting with 2-methyl-1,2,3,4-tetrahydro-4-quinolinol (1.00 g, 6.12 mmol) synthesized in the published manner and 3,4-dimethylbenzoic acid (1.20 g, 7.96 mmol), the same procedure as shown in Reference Example 19 was repeated to give the titled compound (1.13 g, yield: 48%) as an oil. (cis:trans=1:1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(=O)=O.CC(C)=O.[Li]CCCC.[CH:21](=[O:25])[CH2:22][CH2:23][CH3:24]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([CH:21]([OH:25])[CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCC=O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCC(O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A solution of 2,6-dibromopyridine (1.00 g, 4.22 mmol) in THF (40 mL) was cooled to −78° C. (dry-ice/acetone bath) and treated with nBuLi (2.64 mL of a 1.6M solution in hexanes, 4.22 mmol) drop-wise over 10 minutes under nitrogen. After 30 minutes at this temperature the pale yellow/green solution was treated with butyraldehyde (400 μL, 4.44 mmol) drop-wise over 5 minutes and the resulting orange/red solution stirred at this temperature for 1 hour. The solution was then allowed to warm slowly to 0° C. (ice/water bath) over 20 minutes and was then quenched by the drop-wise addition of aqueous HCl (2M, 4 mL). The resulting pale yellow solution was reduced to an oil, partitioned between EtOAc (100 mL) and aqueous HCl (2M, 100 mL), and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with water (150 mL), brine (150 mL), dried (MgSO4), filtered and reduced to an orange/yellow oil. Purification by SPE (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 2:1) afforded the title compound (626 mg).
Reaction SMILES: [CH2:1]([CH2:13][CH2:14][NH2:15])[CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[OH2:16].[F:17][C:18]([F:25])([F:24])[C:19]([O:21]CC)=O>C(#N)C>[F:25][C:18]([F:17])([F:24])[C:19]([NH:15][CH2:14][CH2:13][CH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:19](=[O:16])[C:18]([F:25])([F:24])[F:17])=[O:21]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O
Reactant: NCCCCCCNCCCCCCN
Solvent: CC#N
Product: O=C(NCCCCCCNCCCCCCNC(=O)C(F)(F)F)C(F)(F)F

Procedure:
Bis(hexamethylene)triamine (8.62 g, 40 mmol) was dissolved in acetonitrile (120 ml). Water (0.864 ml) was added to the mixture. Ethyl trifluoroacetate (16.7 ml, 140 mmol) was added to the mixture cooled in an ice bath. After addition, the mixture was refluxed for 16 hours. The solvents were removed by evaporation. The residue solidified upon storing at room temperature and was used for next step without purification.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:27]I>>[CH3:27][O:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: OC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCCOCC1
Reactant: CI
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCCOCC1

Procedure:
Using the procedure described in Example 1, 4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane was reacted with methyl iodide to give 4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane (36), m.p. 69°-70° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25])=[CH:11]1>CN(C)C=O>[C:1]1([NH:7][C:8]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][CH2:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[CH3:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(CCCN)CCc1c[nH]c2ccccc12
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: CN(CCCNC(=O)Nc1ccccc1)CCc1c[nH]c2ccccc12

Procedure:
3 ml phenyl isocyanate are added dropwise between 5° and 10° and with stirring to a solution of 5.8 g N-[2-(3-indolyl)ethyl]-N-methyl-1,3-diaminopropane in 25 ml anhydrous dimethylformamide. The solution is stirred for an hour between 10° and 15° and evaporated. The residue is dried in high vacuum and chromatographed on silicagel using methylene chloride with 6 to 10% methanol, to yield the title compound (M.pt. of the hydrogen maleate 153°-155° with decomposition after crystallization from alcohol/acetone).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[C:17](OC(=O)NC1CCNCC1)(C)(C)C>>[NH2:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:17]2)=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1
Product: NC1CCC(NC(=O)N2CCC(N)CC2)CC1

Procedure:
4-Amino-piperidine-1-carboxylic acid (4-amino-cyclohexyl)-amide is prepared analogously to (R)-3-amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide (Intermediate IF) by replacing (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester with piperidin-4-yl-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:22][CH3:23])=[O:14]
Reactant: CCO
Reactant: O=C(O)CCC(=O)Cc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(=O)Cc1ccc(Cl)cc1Cl
Yield: 46 %

Procedure:
A 1-liter R.B. flask was equipped with a magnetic stirrer and charged with 104.13 g (0.400 mol) of 5-(2',4'-dichlorophenyl)-4-ketopentanoic acid dissolved in 250 ml of ethanol and 250 ml of toluene. To this solution was added 5 ml of concentrated sulfuric acid, and the reaction mixture was refluxed through a Soxhlet extractor containing 300 g of Type 3A molecular sieves for 24 hours. The mixture was cooled and 300 ml of the solvent removed on the Rotary Evaporator. The residue was taken up in 300 ml of ether and washed once with water. The mixture was extracted twice with 150 ml portions of 10% K2CO3 solution, then washed with saturated salt solution, and dried (MgSO4). The solvent was removed on the Rotary Evaporator, and the residue vacuum distilled. The product (52.97 g, 46% yield) was obtained as a slightly yellow viscous oil, b.p. 124°-165° C./0.10-0.30 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:11]([SH:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[C:21](#[N:24])[CH:22]=[CH2:23]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:11](=[S:20])[N:10]([CH2:23][CH2:22][C:21]#[N:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: Cc1ccc(-n2c(-c3ccc(F)cc3)cnc2S)cc1
Solvent: C1COCCO1
Product: Cc1ccc(-n2c(-c3ccc(F)cc3)cn(CCC#N)c2=S)cc1
Temperature: 70 °C

Procedure:
A mixture 5-(4-fluorophenyl)-1-p-tolyl-1H-imidazole-2-thiol (1 eq) in dioxane is stirred and Triton B is added. The mixture is heated to 70° C. and acrylonitrile (1 eq) is added and heated for 3 hours. The cooled mixture is partitioned between aqueous 0.1N HCl and ethyl acetate. The organic layer is washed with water and brine, dried over sodium sulfate, filtered and the solvent removed under reduce pressure. Flash chromatography (SiO2) gives 3-(5-(4-fluorophenyl)-1,2-dihydro-2-thioxo-1-p-tolylimidazol-3-yl)propanenitrile.
Reaction SMILES: [CH:1]1([CH:4]([NH:8]S(C(C)(C)C)=O)[CH:5]([F:7])[F:6])[CH2:3][CH2:2]1.[ClH:15].O1CCOCC1>CO>[Cl-:15].[CH:1]1([CH:4]([NH3+:8])[CH:5]([F:7])[F:6])[CH2:3][CH2:2]1
Reactant: Cl
Reactant: CC(C)(C)S(=O)NC(C(F)F)C1CC1
Solvent: CO
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]C(C(F)F)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(1-cyclopropyl-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide (2.8 g, 12.4 mol) in MeOH (150 mL) was added dropwise 4 M HCl/dioxane (18.6 mL, 74.4 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum, and the solid was washed with Et2O, and dried to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 6.25 (t, 1H); 2.90-3.00 (m, 1H); 1.02-1.12 (m, 1H); 0.78-0.82 (m, 2H); 0.58-0.68 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=[O:33])[C:10](=[CH:29]OCC)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([O:23][CH2:24][CH2:25][O:26][CH3:27])[C:14]=2[Br:28])=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:35]O>C(O)C>[Br:28][C:14]1[C:15]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=1[C:11]([C:10]1[CH:29]=[N:35][O:33][C:9]=1[CH:6]1[CH2:8][CH2:7]1)=[O:12]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)c(OCCOC)c1Br)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)c2cnoc2C2CC2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Sodium acetate (1.65 g) was added to a stirred mixture of 3-cyclopropyl-2-ethoxymethylene- -[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]propan-1,3-dione (8.5 g) and hydroxylamine hydrochloride (1.77 g) in ethanol. The mixture was stirred at room temperature overnight and then evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was chromatographed on silica eluted with a mixture of ethyl acetate and cyclohexane (1:5) to give 4-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylbenzoyl]-5-cyclopropylisoxazole (compound 181) as a yellow oil (3.3 g), NMR (CDCl3), 1.3(2H, m), 1.4(2H,m), 2.6(1H,m), 3.3(3H,s), 3.5(3H,s), 3.9(2H,m), 4.5(2H,m), 7.3(1H,d), 8.0(1H,s), 8.1(1H,d).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH3:34][C:35]1([CH3:53])[CH:44]([N:45]2[C:49]([CH:50]=O)=[CH:48][N:47]=[CH:46]2)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:52])[O:36]1>C1COCC1>[CH3:2][O:3][CH:4]=[CH:50][C:49]1[N:45]([CH:44]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=[O:52])[O:36][C:35]2([CH3:53])[CH3:34])[CH:46]=[N:47][CH:48]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of methoxymethyltriphenylphosphonium chloride (0.974 g, 2.84 mmol) in THF (10 mL) at −78° C. is added sodium hexamethyldisilazide (1M in THF, 3.0 mL, 3.09 mmol) and the mixture is stirred at −78° C. for 1 h. 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.10 g, 0.37 mmol) (Example 9a) in THF (0.2 mL) is then added at −78° C. and the mixture is stirred at ambient temperature overnight. It is then quenched with water and extracted with ethyl acetate. The organic phase is concentrated in vacuo. The residue is purified using by semi-preparative reverse phase HPLC to afford 4-[5-(2-methoxy-vinyl)-imidazole-1-yl]-3,3-dimethyl-isochroman-1-one; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (s, 3 H), 1.52 (s, 3 H), 3.75 (br. s, 3 H), 5.22 (s, 1 H), 5.31 (s, 1 H), 5.55 (br. s, 1 H), 6.82 (br. s, 1 H), 6.96 (br. s, 1 H), 7.16 (d, J=7.6 Hz, 1 H), 7.55 (td, J=7.6, 1.3 Hz, 1 H), 7.63 (td, J=7.6, 1.3 Hz, 1 H), 8.24 (dd, J=7.7, 1.4 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C1CCOc2cc(O)ccc2C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C1CCOc2cc(OCc3cccc(Oc4ccccc4)c3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A solution of ethyl 8-hydroxy-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate (0.189 g, 0.800 mmol), 3-phenoxybenzyl alcohol (0.240 g, 1.20 mmol) and tributylphosphine (0.299 mL, 1.20 mmol) in toluene (8 mL) was stirred under ice-cooling. 1,1′-(Azodicarbonyl)dipiperidine (0.279 g, 1.20 mmol) was added by small portions, and the mixture was stirred under nitrogen atmosphere at room temperature for 8 hr. Hexane (4 mL) was added to the reaction mixture, and the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-20% ethyl acetate/hexane) to give the title compound (0.20 g, yield 60%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].FC(F)(F)C(O)=O.[N:22]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=3)[N:30]=[C:29]2[CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:22]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:43])([F:41])[F:42])[CH:34]=3)[N:30]=[C:29]2[CH:44]2[CH2:45][CH2:46][N:47]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:48][CH2:49]2)[CH2:23][CH2:24][CH2:25]1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: Nc1ncnc(Cl)c1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 120 h
Yield: 46 %

Procedure:
A reaction mixture of 6-Chloro-5-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-ylamine (45.00 mg; 0.20 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (123.48 mg; 0.20 mmol; 1.00 eq.), and Cs2CO3 (257.71 mg; 0.79 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 5 days. Purified by HPLC, collected title product 54 mg, yield 39.8%. LC-MS: (M+1=588, obsd.=588).