Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].N#N.[CH3:14][CH2:15][OH:16].[Li][CH:18](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH2:14][C@H:15]([OH:16])[CH3:18]
Reactant: [Li]C(C)CC
Reactant: COc1ccc(OC)c(Br)c1
Reactant: CCO
Agent: FB(F)F
Agent: N#N
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COc1ccc(OC)c(C[C@@H](C)O)c1
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of 2-bromo-1,4-dimethoxybenzene (4.35 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.45 in EtOAc/hexane 3:7) to give (2R)-1-(2,5-dimethoxyphenyl)propan-2-ol (2.78 g, 71%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 6.79 (m, 1H), 6.74 (m, 2H), 4.05 (m, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 2.65-2.86 (m, 2H), 2.10 (d, J=3.39 Hz, 1H), 1.22 (d, J=6.21 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[CH3:35][NH2:36].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:35][NH:36][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:28])=[O:29])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCOC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (25 mg, 0.055 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added methyl amine (0.15 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (13.2 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1%/o trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (9.0 mg, 36%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: Oc1cc(Cl)ccn1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCO[C@@H]1CN(c2cc[nH]c(=O)c2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 5.4 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 4-chloro-2-hydroxypyridine (46 mg, 0.36 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMSO (1 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 6.3 mg of the title compound as a pale yellow amorphous solid (5%).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:19][C:20]([OH:22])=O)[C:9](=[O:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]([CH2:19][C:20]([Cl:25])=[O:22])[C:9](=[O:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Temperature: 25 °C

Procedure:
A mixture of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid (2.1 g, 7.1 mmol) [J. Org. Chem., 38, 3034 (1973)], thionyl chloride (5 ml) and methylene chloride (20 ml) is refluxed for 2.5 hours. After cooling to room temperature the solvent is removed in vacuo and resulting oil crystallizes on standing. The product is triturated with ether-hexane to give 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride; 2.0 g mp 104°-112°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([OH:16])=[O:15])#[N:2].C(N/C(=N/C(C)C)/O[C:23]([CH3:26])([CH3:25])[CH3:24])(C)C>C1COCC1.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15])#[N:2]
Reactant: N#Cc1cc2c(cc1F)OCCC2C(=O)O
Reactant: CC(C)/N=C(/NC(C)C)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1CCOc2cc(F)c(C#N)cc21
Reaction time: 3 h
Yield: 64 %

Procedure:
6-Cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid was dissolved in 10 mL of THF and treated with (Z)-tert-butyl N,N′-diisopropylcarbamimidate. After stirring for 3 hours, an additional 2 mL of (Z)-tert-butyl N,N′-diisopropylcarbamimidate was added and the reaction was stirred overnight. The reaction was diluted with ether, filtered, concentrated onto silica gel and flashed with 8:1 hexanes/ethyl acetate to provide the desired product (1.4 g, 64% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH:31]C(=O)OC(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:31][CH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:22]([C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=3[N:10]=2)=[O:6])=[CH:3][C:2]=1[Cl:1])=[O:24]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl pyrrolidin-2-ylmethylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 2.98 minutes; C21H21Cl2N5O2 (446.34); mass spectrum: (M+H)+=446.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].[CH2:15]([O:17]C=O)C.[H-].[Na+].C(OCC)(=O)C>COCCOC>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH:15]=[O:17])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(C)nc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C=O)Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 16.0 g (0.083 mole) of 3-(6-methyl-3-pyridyl)-propionic acid ethyl ester and 9.6 g (0.13 mole) of formic acid ethyl ester is slowly added dropwise while cooling with ice to a suspension of 5.2 g of sodium hydride (80% on paraffin oil; 0.17 mole) in 30 ml of ethylene glycol dimethyl ether. On completion of the addition, the solution is stirred for 8 hours at room temperature. After the addition of 10 ml of ethyl acetate and 200 ml of ice water, the mixture is extracted three times with diethyl ether. The aqueous phase is diluted to pH 5.4 with dilute hydrochloric acid and the crystals precipitating are filtered under suction. Light brown crystals melting at 141°-142° C. are obtained in a yield of 12.8 g (70%).
Reaction SMILES: I[CH2:2][CH3:3].[Cl:4][C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.C([O-])([O-])=O.[K+].[K+].[CH3:20][N:21](C=O)C>>[Cl:4][C:5]1[C:6]([O:13][CH2:2][CH3:3])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][CH2:20][NH2:21]
Reactant: CCI
Reactant: CN(C)C=O
Reactant: O=Cc1cccc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1c(Cl)cccc1CCN
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 91 %

Procedure:
Iodoethane (1.54 mL, 19.2 mmol) was added to a stirring solution of 3-chloro-2-hydroxy-benzaldehyde (2.01 g, 12.8 mmol) and K2CO3 (3.90 g, 28.2 mmol) in DMF (25 mL). The mixture was heated to 50° C. and stirred for 2.5 h. The heat was removed and reaction stirred at room temperature for 18 h. The reaction was quenched with H2O (70 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (2.16 g, 91%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.85 (dd, J=7.8, 1.5 Hz, 1H), 7.72 (dd, J=7.8, 1.8 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 1.39 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1([CH3:14])[C:11](=[O:12])[CH2:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([CH3:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[CH2:1]([C:8]1([CH3:14])[C:9](=[O:13])[C:10]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]2[NH:28][C:29]3[C:34]([C:26]=2[CH2:25][C:24]([NH:37][C:38](=[O:40])[CH3:39])([CH3:23])[CH3:36])=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=3)=[C:11]1[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(C)Cc1c[nH]c2cc(C)ccc12
Reactant: CC1(Cc2ccccc2)C(=O)CC1=O
Reactant: O=Cc1ccccc1
Product: CC(=O)NC(C)(C)Cc1c(C(C2=C(O)C(C)(Cc3ccccc3)C2=O)c2ccccc2)[nH]c2cc(C)ccc12

Procedure:
Using general procedure C, 2-benzyl-2-methyl-cyclobutane-1,3-dione (Lit. 1) was reacted with benzaldehyde and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-acetamide (from Example 1.2) to give the title compound as a red solid. MS: 519.5 ([M−H]−).
Reaction SMILES: C([Li])CCC.C[Si]([C:10]#[CH:11])(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].N>O1CCCC1.CCCCCC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21]([C:10]#[CH:11])([OH:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CC1(O)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
In a dry ice-acetone bath, 40 ml of a 1.6 M hexane solution of n-butyllithium was added dropwise to a solution of 6.07 g of trimethylsilylacetylene in 100 ml of tetrahydrofuran. After the temperature was once elevated to 0° C., the mixture was cooled again in a dry ice-acetone bath and a solution of 5.97 g of 1-tert-butoxycarbonylpiperidin-3-one in 50 ml of tetrahydrofuran was added dropwise thereto. After 1 hour, aqueous ammonia chloride was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography with 30% ethyl acetate/hexane. To the resulting compound were added 10 g of anhydrous potassium carbonate and 100 ml of methanol, followed by stirring for 2 hours. Water was added thereto, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated, to give 4.8 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH3:8][C:9]([CH3:11])=[O:10].C1OC1C>C[Si](C)(C)N[Si](C)(C)C.Cl.O.C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:9]([OH:10])([CH3:11])[CH3:8])(=[O:7])[OH:6]
Reactant: CC(C)=O
Reactant: NCCCP(O)O
Agent: CC1CO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(O)P(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A suspension of 1.23 g 3-aminopropylphosphonous acid in 25 ml of hexamethyldisilazane is heated to reflux under an inert gas for 20 hours. After this time a clear solution results and the reaction mixture is cooled to room temperature under inert gas and 50 ml of anhydrous acetone is added and an exothermic reaction results. The reaction mixture is allowed to cool to room temperature and the volatile components removed invacuo to afford a clear oil. This oil is dissolved in 50 ml of a 2.0M hydrochloric acid solution in water and washed with 2×100 ml of dichloromethane and 1×100 ml of ether. The aqueous layer is evaporated to dryness to give a semi-solid residue which is co-evaporated with water (10×20 ml) and absolute ethanol (10×20 ml) yielding3-aminopropyl(2-hydroxyprop-2-y)phosphinic acid hydrochloride m.p. 159°-161° as a white solid. This is suspended in absolute ethanol and treated with propylene oxide. Filtration and drying of the solid affords 3-aminopropyl(2-hydroxyprop-2 -yl)phosphinic acid; m.p. 243°-244°.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[CH2:34][CH2:33]2>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[C:35](=[O:39])[CH2:34][CH2:33]3)[N:10]=[CH:9]1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C1CCc2cc(OCCCc3c[nH]cn3)ccc21

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of 5-hydroxy-1-indanone are treated as described in Example 56.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4](F)[N:3]=1.[CH3:10][O-:11].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: Fc1cc(I)cc(F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(I)cc(F)n1
Temperature: 25 °C

Procedure:
To a solution of 2,6-difluoro-4-iodopyridine (7.37 g, 30.6 mmol) in tetrahydrofuran (200 ml) cooled to 0° C. was added a 0.5 M solution of sodium methoxide (61.2 ml, 30.6 mm) in methyl alcohol. After 4 h the reaction mixture was warmed to ambient temperature. LRMS indicated incomplete conversion to product and additional 0.5 M sodium methoxide solution in methyl alcohol (6.12 ml, 3.06 mmol) was added. After 1 hour the reaction mixture was quenched with water (50 ml), partially concentrated, diluted with ethyl ether, washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated to afford 2-fluoro-4-iodo-6-methoxypyridine as a yellow oil which was used without further purification. 1H NMR (600 MHz, DMSO-d6) δ 7.19 (s, 1H); 7.16 (d, 1H); 3.78 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([Cl:34])=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([C:44](=[O:52])[CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[ClH:34].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:50][CH2:51][N:46]([CH2:45][C:44]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[O:52])[CH2:47][CH2:48]3)=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)Cl)cc1
Product: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)cc1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12c) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 686.6 [(M+H)+]
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:33]Cl)[N:26]([CH2:27][C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>CN(C=O)C>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:33][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[N:26]([CH2:27][C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1(O)CCC1
Agent: [K]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2c1nc(CN1C(=O)c3ccccc3C1=O)n2CC1(O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, potassium phthalimide (1.21 g, 6.52 mmol) was added to a solution of 1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (1.88 g, 5.93 mmol) in DMF (30 mL), and the reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was partitioned between chloroform (200 mL) and water (25 mL)/saturated aqueous sodium bicarbonate (2×40 mL). The organic layer was washed with brine (2×40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 2.42 g of 2-({4-amino-1-[(1-hydroxycyclobutyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:14]#[N:15])([CH3:13])[CH3:12])(C)(C)C.ClS(N=[C:22]=[O:23])(=O)=O.[OH2:24]>ClCCl.CO>[NH2:7][CH2:8][CH2:9][N:10]1[C:11]([CH3:12])([CH3:13])[C:14](=[O:24])[NH:15][C:22]1=[O:23]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C#N)NCCNC(=O)OC(C)(C)C
Reactant: O
Solvent: ClCCl
Solvent: CO
Product: CC1(C)C(=O)NC(=O)N1CCN
Temperature: 101 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
{2-[(Cyano-dimethyl-methyl)-amino]-ethyl}-carbamic acid tert-butyl ester (31.7 g, 139.5 mmol) was dissolved in dichloromethane (500 mL) and the stirred solution was cooled in an ice bath. After 15 min, chlorosulfonyl isocyanate (14.5 mL, 23.6 g, 167 mmol) was added by syringe over 2 min, and the resulting solution was stirred for an additional 30 min. The solution was concentrated in vacuo to give a pale yellow gum. Water (500 mL) was added, and the mixture was heated in an oil bath (bath temperature 101° C.) for 20 h, during which time the solid went into solution. The resulting pale brown solution was cooled and allowed to stand for 30 min before filtering through a fluted filter paper (removes a trace amount of an oily residue). The solution was applied to a 3″ diameter flash column packed with SCX ion exchange resin (800 g; Varian Cat# 12213040) which had been previously conditioned with MeOH (2 L) followed by water (2 L). The resin was washed with water (2 L) followed by MeOH (2 L), and the product was then eluted with 2 M NH3 in MeOH (2.4 L). Concentration in vacuo gave the product as a pale brown hygroscopic foam. This was dissolved in MeOH (150 mL), filtered through a fluted filter paper, and concentrated in vacuo to give pure product (16.7 g, 70%). Final purification was achieved by flash chromatography (DCM:MeOH:NH4OH; 80:20:1 v/v/v) to give a fluffy white solid. 1H NMR: δ (d6-DMSO, 400 MHz) 3.60 (bs, NH & H2O), 2.93 (2 H, t, CH2), 2.45 (2 H, t, CH2), 1.06 (6 H, S, C(Me)2). MS (M+H)+ 172.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl>CS(C)=O>[CH:2]([C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4]1)=[O:1]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO)CCC3)CC2)c2ncnn12
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C=O)CCC3)CC2)c2ncnn12
Reaction time: 3 h

Procedure:
To a mixture of 4′-{[4-(trans-4-{[1-(hydroxymethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.7 g), triethylamine (0.86 mL) and dimethyl sulfoxide (10 mL) was added a solution (5 mL) of sulfur trioxide-pyridine complex (0.59 g) in dimethyl sulfoxide at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.7 g, 100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:21])[C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:7][CH:6]=1.[I:32]I.Cl>[NH4+].[OH-].CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[C:15]([I:32])[C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:21])[C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:7][CH:6]=1
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: II
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-(2-Bromoethoxy)-benzyl)-3-(2,4-dichlorophenyl)-7-hydroxy-chromen-2-one (2.734 g, 5.26 mmol) in NH4OH (22 mL), MeOH (55 mL) and CH2Cl2 (33 mL) was added I2 (1.334 g, 5.26 mmol), and the resulting mixture was stirred at r.t for 30 min. Aqueous 4 M HCl was then added to lower the pH of the aqueous layer to 5. The resultant layers were separated and the aqueous phase was extracted with AcOEt (3×). The combined organic layers were washed with brine (2×), dried (MgSO4) and concentrated in vacuo. The residual beige solid (3.25 g, 96%) was used directly in the next step without further purification. 1H NMR (300 MHz, DMSO) δ 11.43 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.51–7.42 (m, 3H), 7.02 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.5 Hz, 2H), 4.21 (t, J=5.0 Hz, 2H), 4.04 (d, J=15.5 Hz, 1H), 3.73 (t, J=5.0 Hz, 2H), 3.70 (d, J=15.5 Hz, 1H); MS (ESI) m/z 642.7 (M−H)−; HPLC tR 7.27 min.