Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([I:11])[C:3]=12.S(O[CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[CH:9]=[C:10]([I:11])[C:3]=12
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Brc1ccnc2[nH]cc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(Br)ccnc32)C1
Temperature: 95 °C
Yield: 32.8 %

Procedure:
To a mixture of 4-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (D6) (500 mg, 1.548 mmol) and tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (D100) (558 mg, 1.703 mmol) in DMSO (10 mL) was added cesium carbonate (1513 mg, 4.64 mmol). The final mixture was heated at 80° C. for 4 hours after which the temperature is increase to 95° C. and the mixture heated overnight. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×3). The combined organics were dried over magnesium sulfate and concentrated. The crude was purified on normal phase silica eluting with ethyl acetate and cyclohexane (0-50%) to give the title compound (243 mg). LCMS (A): m/z (M+H)+ 478/480, C15H17BrIN3O2 requires 477/479 (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10](Cl)=[N:9][N:8]=1.Br.[C:25](=[O:28])([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:6]([CH2:5][CH2:4][CH2:25][OH:28])[CH3:7])=[N:9][N:8]=[C:7]2[NH:6][CH2:5][C:4]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(Cl)cc23)cc1Cl
Agent: Br
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2nnc(N(C)CCCO)c3ccc(Cl)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 7.5 h
Yield: 6.5 %

Procedure:
The compound (1.0 g, 2.7 mmol) prepared in Example 27 was dissolved in 9 ml of N-methyl-2-pyrrolidone, followed by the addition of 0.7 g (4.1 mmol) of N-methylpropanolamine hydrobromide and 1.14 g (8.2 mmol) of anhydrous potassium carbonate. The obtained mixture was stirred at 170° C. for 7.5 hours, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by distillation. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (20:1)] and crystallized from dichloromethane/ether to give 37 mg of the title compound as white needles.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH2:13][CH3:14])[C:10]([CH:17]3[CH2:19][CH2:18]3)([C:15]#[N:16])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][CH3:14])[C@@:10]([CH:17]3[CH2:19][CH2:18]3)([C:15]#[N:16])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1
Reactant: CCC1CN(c2ccnc(Cl)n2)C(=O)C1(C#N)C1CC1
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC[C@H]1CN(c2ccnc(Cl)n2)C(=O)[C@@]1(C#N)C1CC1
Yield: 38.5 %

Procedure:
To a mixture of 3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (3.7 g) obtained in Step B of Example 376, 2,4-dichloropyrimidine (3.1 g), cesium carbonate (13 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.71 g) in tetrahydrofuran (55 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.38 g), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3SR,4RS)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) and (3SR,4SR)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g). (3SR,4RS)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (500 mg) having a shorter retention time and (3R,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (510 mg) having a longer retention time. (3SR,4SR)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (560 mg) having a shorter retention time and (3R,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (600 mg) having a longer retention time.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][N:5]=[N+:6]=[N-:7].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=O)[S:13][CH:14]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:8])[C:4]([N:5]=[N+:6]=[N-:7])=[CH:15][C:12]1[S:13][CH:14]=[C:10]([Br:9])[CH:11]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cc(Br)cs1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of azido-acetic acid methyl ester (25 g, 220 mmol) and 15 g of 4-bromo-thiophene-2-carbaldehyde (14.0 g, 73 mmol) in 50 ml of MeOH cooled at −25° C. was added a solution NaOMe in MeOH (51 ml, 4.36 M). The resulting mixture (slush) was stirred with a mechanical stirrer for 2 h at 0° C. and the 200 g of ice was added. The yellow solid was collected by filtration and air-dried to give 15 g of the title product which was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:3]([NH2:5])=[O:4].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C:6]2[C:11](=[CH:10][C:9]3[O:12][CH2:13][O:14][C:8]=3[CH:7]=2)[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:5][C:3]1=[O:4]
Reactant: CN(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3
Yield: 20 %

Procedure:
A mixture of N-methyl-N-[3,4-(methylenedioxy)phenyl]urea (240 mg), benzaldehyde (140 μL) and methanesulfonic acid (50 μL) and toluene (60 mL) was refluxed for 2 h in a flask equipped with a Dean-Stark water separator. After cooling, the solution was washed with water thoroughly, dried over Na2SO4 and concentrated in vacuo. The resulting solid was recrystallized from chloroform/hexane to provided the title compound as a tan solid (70 mg, 20%), mp: 228-230° C. 1H NMR (CDCl3): 7.37-7.30 (m, 5H), 6.53 (s, 1H), 6.28 (s, 1H), 5.91 (d, 1H, J=1.4), 5.89 (d, 1H, J=1.4), 5.46 (s, 1H), 5.11 (br s, 1H), 3.33 (s, 3H). Anal. calcd. for C16H14N2O3: C, 68.08: H, 5.00; N, 9.92. Found: C, 68.06; H, 4.91; N, 9.71.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[NH:14][C:13]1=[O:20])[C:6]2=[O:11].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O.[BH4-].[Na+]>C(O)(=O)C>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[NH:14][C:13]1=[O:20])[C:6]2=[O:11]
Reactant: O=Cc1ccco1
Reactant: Nc1cccc2c1CN(C1CC(O)C(=O)NC1=O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(N2Cc3c(NCc4ccco4)cccc3C2=O)CC1O
Reaction time: 18 h

Procedure:
A solution of 3-(4-amino-1-oxoisoindolin-2-yl)-5-hydroxypiperidine-2,6-dione (0.82 g, 3.0 mmol) and 2-furaldehyde (0.34 g, 3.5 mmol) in acetic acid (10 mL) is heated at reflux for 4 hours. To the mixture is added sodium borohydride (130 mg, 3.5 mmol) at room temperature and kept for 18 hours. The mixture is worked up to give 3-(4-fur-2-ylmethylamino-1-oxoisoindolin-2-yl)-5-hydroxypiperidine-2,6-dione which is further purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[NH:30]([C:14]1[N:13]=[C:12]2[N:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10](=[O:29])[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 180 °C
Yield: 11.3 %

Procedure:
A mixture of 40 mg (0.096 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one and 1 ml (11 mmol) of aniline was heated at 180° C. for 45 minutes, cooled and partitioned between 30 ml of ethyl acetate and 30 ml of 2M hydrochloric acid. The separated organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution. Product-containing fractions were combined and evaporated to give a tan solid which was purified further by HPLC. The mobile phase was water/0.1% trifluoroacetic acid (A) and acetonitrile/0.07% trifluoroacetic acid (B); the gradient was 5%-95% B over 20 minutes; and the product was detected with an ultraviolet detector at a wavelength of 215 nm. The product-containing fraction was lyophilized to give 5 mg (4%) of 7-anilino-3-(2,6-dichlorophenyl)-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 138° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1.[CH3:30][NH2:31]>CO>[CH3:30][NH:31][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:11][CH2:12]2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]=1
Reactant: CN
Reactant: Clc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Solvent: CO
Product: CNc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 2-chloro-1-[1-(1-phenylcycloheptyl)-4-piperidinyl]benzimidazole (Example 1, 69.3 mg, 0.17 mmol) in 40% MeNH2 solution in MeOH (5 ml) was stirred in autoclave at 110° C. for 6 h. After cooling down to room temperature, the solvent was evaporated and the residue was purified by preparative TLC (0.5 mm plate×3, CH2Cl2/MeOH:10/1) to give 56.9 mg(83%) of title compound as pale brown amorphous solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1([N:13]([CH:35]2[CH2:37][CH2:36]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]([NH2:31])=[S:30])=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:12][CH2:11]1>>[CH:35]1([N:13]([CH:10]2[CH2:11][CH2:12]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]4[S:30][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:31]=4)=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:36][CH2:37]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1csc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)n1

Procedure:
This compound was prepared according to example 2 using ethyl bromopyruvate and N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) to yield ethyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-4-carboxylate as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(F)ccc2[nH]1
Product: Fc1ccc2nc(Cl)ccc2c1

Procedure:
A mixture of the so-prepared 6-fluorocarbostyril (2.9 gm, 0.018 mole) and 30.0 ml of phosphorous oxychloride was refluxed for 1.5 hr. Most of the excess phosphorous oxychloride was then distilled off under aspirator vacuum and the residue poured over crushed ice. The reaction mixture was made nearly neutral with 50% sodium hydroxide. The crude solid product was collected by filtration, taken up in
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH3:35])[C:23](=[O:24])[CH2:22][N:14]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=1)(=[O:12])=[O:13])[C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(C)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][C:11](=[O:13])[O:17][C:15](=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Product: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Yield: 92 %

Procedure:
Heat a combination of the product of Step 2 (100 g) and acetyl chloride (300 mL) at reflux for 5 hours. Cool the reaction mixture, azeotrope with toluene, and concentrate under reduced pressure. Slurry he residue with Et2O (250 mL) and filter to afford 3-(3,4-dichlorophenyl)-glutaric anhydride (86 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(F)cc1Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1ccc(F)cc1Cl
Yield: 96.7 %

Procedure:
1.64 g (6 mmol) of 2-chloro-4-fluorobenzamide were dissolved in 3 ml of dichloromethane and, at 0° C. and under a nitrogen atmosphere, 0.8 ml (9.3 mmol) of oxalyl chloride was added, and the mixture was heated to reflux for 9 hours. The reaction mixture was concentrated under high vacuum and afforded 1.17 g (5.8 mmol) of the desired product, which was employed as solution in dichloromethane (1 mmol in 1.7 ml of solution) in stage b.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][CH2:45][CH:46]=[CH2:47])=[O:43])[CH2:38][CH2:37]1)=[O:35])=[O:6])[CH:2]=[CH2:3].C([SiH](CC)CC)C>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([SH:12])[CH2:9][C@H:8]1/[CH:32]=[CH:33]/[C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:42]([O:44][CH2:45][CH:46]=[CH2:47])=[O:43])[CH2:40][CH2:41]1)=[O:35])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCN(C(=O)/C=C/[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCC=C)CC1
Agent: CC[SiH](CC)CC
Product: C=CCOC(=O)N1CCN(C(=O)/C=C/[C@@H]2C[C@H](S)CN2C(=O)OCC=C)CC1
Yield: 100 %

Procedure:
The same operation as in Reference Example 4-2) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-[(E)-2-[4-(allyloxycarbonyl)piperazinylcarbonyl]vinyl]-4-tritylthiopyrrolidine (the compound obtained in Reference Example 8-1); 1.97 g, 3.02 mmol) and triethylsilane (0.51 ml, 3.17 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with acetone-ethyl acetate 1:2) to give the title compound (1.24 g, 100% yield) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([I:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][CH2:15][CH2:16][N:17]1[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:18]1=[O:25].C(N(CC)CC)C>CC(O)C>[I:13][C:10]1[S:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:22])([CH3:23])[C:20](=[O:24])[NH:19][C:18]3=[O:25])[N:7]=2)=[CH:12][CH:11]=1
Reactant: Clc1nccc(-c2ccc(I)s2)n1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1

Procedure:
A solution of 205 mg (0.64 mmol) of 2-chloro-4-(5-iodothiophen-2-yl)pyrimidine, 186 mg (1.1 mmol) of 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione and 0.15 mL (1.1 mmol) of triethylamine in 5 mL of iPrOH was heated in a microwave to 180° C. for 10 min then concentrated in vacuo. The crude solid product was purified by flash chromatography eluting with a linear gradient of 40% EtOAc in hexane to 100% EtOAc to deliver the title compound. MS (M+H)+ 458.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[CH:27][CH:26]=1>CCOCC>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]=[CH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:4]=2)=[O:35])=[CH:29][CH:30]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-fluoro-3-phenoxybenzyl alcohol (0.22 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20 percent ether/hexane, gives 4-fluoro-3-phenoxybenzyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:28])=O>ClCCl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[N:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][Cl:28])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CO)cc3)nc2)CC1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of (4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)methanol (227.0 mg, 0.669 mmol) in dichloromethane (5 ml) was added thionyl chloride (0.096 ml, 1.331 mmol). After stirring at room temperature for 2 hrs, the reaction mixture was concentrated. To the residue was added aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness to give 1-acetyl-4-(6-{2-[4-(chloromethyl)phenyl]ethyl}pyridin-3-yl)piperazine (234.8 mg, yield 98.1%) as a silghtly yellow solid.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C@H:9]([CH3:18])[N:10]2[C:15](=[O:17])[CH3:16].Cl>CO>[OH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C@H:9]([CH3:18])[N:10]2[C:15](=[O:17])[CH3:16]
Reactant: COCOc1cccc2c1CC[C@H](C)N2C(C)=O
Agent: Cl
Solvent: CO
Product: CC(=O)N1c2cccc(O)c2CC[C@@H]1C
Temperature: 50 °C
Yield: 93.3 %

Procedure:
A solution of (S)-1-(5-(methoxymethoxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.6 g, 6.42 mmol) in methanol (16 mL) was treated with concentrated hydrochloric acid (1.0 mL, 12.8 mmol) at rt. The solution was heated to 50° C. for 90 min. Heating was discontinued, and the solution was allowed to slowly cool to room temperature overnight. Methanol was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous layer was separated and extracted with dichloromethane. The combined organic extracts were concentrated under reduced pressure. The residue was dissolved in acetonitrile (ca. 20-30 mL), and then concentrated under reduced pressure to afford (S)-1-(5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.23 g, 93%) as an off-white to tan solid. MS (ESI, pos. ion) m/z 206 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.[N:35]1(OC(N(C)C)=[N+](C)C)[C:39]2C=CC=CC=2N=N1.CN>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:35][CH3:39])=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 6 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (300 mg, 0.82 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (341 mg, 0.9 mmol) and methylamine (45 mL, 0.9 mmol); (15 mg, 6% yield). RT 7.164 20-100% ODS at 1 mL/min method, ES-MS (m/z) 292 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[F:8][C:9]1[C:14]([S:15](Cl)(=[O:17])=[O:16])=[C:13]([F:19])[C:12]([F:20])=[C:11]([F:21])[C:10]=1[F:22].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[C:12]([F:20])=[C:13]([F:19])[C:14]=1[S:15]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(O)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-methyl-1,3-butane diol (0.79 g, 7.5 mmol) and TEA (0.37 g, 3.6 mmol) in CH2Cl2 (7 mL) at) 0° C. was added pentafluorobenzenesulfonyl chloride (0.80 g, 3.0 mmol). The solution was stirred at 0° C. for 1.5 h. Saturated aqueous NaHCO3 (10 mL) was added to the solution and the mixture was stirred at rt for 15 min. The organics were extracted with CH2Cl2 and washed with 0.5 M HCl (1×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with (30% ethyl acetate in hexanes) yielded the desired product as a white crystalline low melting point solid (0.69 g, 66%). 1H NMR (400 MHz CDCl3) δ 4.49 (t, 2H, J=7.0 Hz), 1.97 (t, 2H, J=7.0 Hz) 1.27 (s, 6H). Anal. Calcd. For C11H11F5O4S: C, 39.53; H, 3.32. Found: C, 39.54; H, 3.22.