Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].[CH3:21][N:22]1[C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:24]=[C:23]1[CH:40]=[O:41].C(N(CC)CC)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:40]([C:23]1[N:22]([CH3:21])[C:26]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:9]=2[NH:10][C:11]2[C:12]([CH3:20])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[C:7]#[N:8])=[CH:25][N:24]=1)=[O:41]
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C=O)n1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1c(Nc2c(C#N)cncc2-c2cnc(C=O)n2C)ccc2[nH]ccc12
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of 5-iodo-4[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (250 mg, 0.67 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole-2-carbaldehyde (see e.g., U.S. Pat. No. 6,521,618) (401 mg, 1.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (24 mg, 0.034 mmol), and triethylamine (74.9 mg, 0.74 mmol) in dioxane (6 mL) was heated at the reflux temperature for 22 h, cooled to room temperature, and concentrated in vacuo. The residue was suspended in CH2Cl2 and filtered and the solid was washed with CH2Cl2. The combined filtrate and washings were concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/CH2Cl2, 20% to 90%; MeOH/ethyl acetate, 5%) to provide 103 mg (43%) of 5-(2-formyl-1-methyl-1H-imidazol-5-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 537 as a dark yellow solid. MS: 355.2 (M+H); melting range: 200-202° C.; and HRMS: 357.1458.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([O:25][C@@H:26]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=4[Cl:36])[CH3:27])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:36][C:29]1[C:30]([F:35])=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C@H:26]([O:25][C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[CH:24]=1)[CH3:27]
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (11.8 g, 21.45 mmol) in CH2Cl2 (59 mL, 0.2M) was added 4N HCl/Dioxane (21 mL). The solution was stirred overnight forming a solid. The solid was crushed thoroughly with a glass rod and sonicated to release starting material trapped in the solid. Additional 4N HCl/Dioxane (21 mL) was added and stirred for another 2 hours at room temperature in which LCMS showed no starting material. The suspension was filtered in a Buchner funnel lined with filter paper. The mother liquor was saved because it contained <5% of product. The solid was transferred to a 500 mL beaker and HPLC water was added until the solid dissolved completely. The pH was adjusted to 10 with the addition of solid Na2CO3. The water solution was extracted with CH2Cl2 (5×200 mL) or until LCMS showed no product in the aqueous layer. The CH2Cl2 solution was dried over Na2SO4 and concentrated. The crude product, re-dissolved in CH2Cl2 (10 mL) and MeOH (1 mL), was purified on a silica gel column eluting with CH2Cl2/MeoH/NEt3 system (Biotage 40+Column: equilibrium 600 mL CH2Cl2 100% giving byproduct, segment 1: 1200 mL 10% MeOH/CH2Cl2 linear, segment 2: 2400 mL 10% MeOH/CH2Cl2 step, segment 3: 2400 mL 9% MeOH/1% NEt3/CH2Cl2). The desired fractions were collected to provide 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (7.19 g, 75% combined yield, white solid). MS m/e 450 (M+1)+. 1H NMR (DMSO-d6, 400 MHz) δ 7.92 (s, 1H), 7.76 (s, 1H), 7.58 (m, 1H), 7.53 (s, 1H), 7.45 (m, 1H), 6.90 (s, 1H), 6.10 (m, 1H), 5.55 (bs, 2H), 4.14 (m, 1H), 3.05 (m, 2H), 2.58 (m, 2H), 1.94 (m, 2H), 1.80 (d, 3H), 1.76 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[N:3]=[C:4]([CH3:6])[CH3:5].[Li+].CCC[CH2-].[Cl:13][C:14]1[C:15]([O:24][C:25]2[CH:35]=[CH:34][C:28]([O:29][CH:30]([CH3:33])[CH:31]=[O:32])=[CH:27][CH:26]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(O)(=O)C>C1COCC1>[CH3:1][N:2]([CH3:7])[N:3]=[C:4]([CH2:6][CH:31]([OH:32])[CH:30]([O:29][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:15]2[C:14]([Cl:13])=[CH:19][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:17][N:16]=2)=[CH:35][CH:34]=1)[CH3:33])[CH3:5]
Reactant: CC(C=O)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: CC(C)=NN(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)=NN(C)C
Reaction time: 0.5 h

Procedure:
To a solution of acetone N,N-dimethylhydrazone (0.48 g, 4.8 mmol) in 5 ml of THF is added N-butyllithium (4.8 mmol) at -65°, and the mixture is stirred for about 30 minutes. 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propanal (1.50 g, 4.8 mmol) in 5 ml of THF is added dropwise. After several hours at -65°, the reaction mixture is allowed to warm to 0° and is poured onto ice made slightly acidic with 10% acetic acid. The organic phase is separated, washed with water and with NaCl and dried. Solvent is removed to give 4-hydroxy-5-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-2-hexanone N,N-dimethylhydrazone.
Reaction SMILES: N[C:2]1[NH:7][C:6]2=[CH:8][CH:9]=[N:10][C:5]2=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.N1C=CC=CC=1.[FH:25].N(OC(C)(C)C)=O.[Br:33]N1C(=O)CCC1=O>N1C=CC=CC=1.O1CCCC1>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([F:25])[NH:7][C:6]2=[C:8]([Br:33])[CH:9]=[N:10][C:5]=12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: F
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OCc2ccccc2)c2nccc-2[nH]1
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Fc1nc(OCc2ccccc2)c2ncc(Br)c-2[nH]1

Procedure:
A solution of 2-amino-4-benzyloxypyrrolo[3,2-d]pyrimidine (0.85 g) (Example 12) in dry pyridine (20 mL) was treated with hydrogen fluoride-pyridine and tert-butyl nitrite as described in Example 13. A solution of the crude product in tetrahydrofuran (30 mL) was cooled in an ice bath while N-bromosuccinimide (0.6 g) was added portion-wise. The solution was concentrated and chromatography afforded 4-benzyloxy-7-bromo-2-fluoropyrrolo[3,2-d]pyrimidine (0.8 g) as a solid. A solution of this material (0.74 g) in tetrahydrofuran (30 mL) was cooled in an ice bath while sodium hydride (0.11 g, 60% dispersion) and then tert-butyldimethylsilyl chloride (0.41 g) were added. After 1 h methylene chloride (50 mL) was added and the reaction was quenched with water, then washed with additional water. Normal processing and chromatography afforded 4-benzyloxy-7-bromo-5-N-tert-butyldimethylsilyl-2-fluoropyrrolo[3,2-d]pyrimidine (0.82 g) as a solid. 13C NMR (CDCl3) δ 158.4 (JC,F=17 Hz), 157.5 (JC,F=212 Hz), 153.5 (JC,F=16 Hz), 137.7, 134.9, 130.5, 129.4, 129.0, 118.0, 93.3, 70.3, 26.6, 19.2, −1.9, −2.3.
Reaction SMILES: C(N(CC)CC)C.[Si]([C:15]#[C:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2(O)[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[F:31])(C(C)(C)C)(C)C.CS(Cl)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.O>[C:16]([C:17]1[C:18]([F:31])=[CH:19][C:20]([C:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH:24]=2)=[CH:21][N:22]=1)#[CH:15]
Reactant: CC1CCC(O)(c2cnc(C#C[Si](C)(C)C(C)(C)C)c(F)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1ncc(C2=CCC(C)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.28 mL (2.00 mmol) of triethylamine was added to a solution of 348 mg (1.00 mmol) of 1-{6-[(tert-butyldimethylsilanyl)ethynyl]-5-fluoropyridin-3-yl}-4-methylcyclohexanol in 15 mL of DCM and then 0.15 mL (2.00 mmol) of methanesulfonic acid chloride was added dropwise while the mixture was cooled. The reaction was stirred for 2 hours at RT and then a further 0.15 mL (2.00 mmol) of methanesulfonic acid chloride were added and the mixture was stirred for 1 hour at RT. A further 0.58 mL (4.00 mmol) of triethylamine was added and the mixture was stirred for 1 hour at RT. The reaction mixture was combined with 50 mL of ice water. The organic phase was separated off, washed with water, and the solvent was removed in vacuo. The residue was dissolved in 25 mL of DCM and combined with 315 mg (1.00 mmol) of TBAF. The solution was stirred for 30 minutes at RT and then combined with water. The organic phase was separated off, washed several times with water, dried over magnesium sulfate, and the solvent was eliminated in vacuo. Yield: 130 mg (45% of theoretical; 75% content of product); C14H14FN (M=215.266); calc.: molpeak (M+H)+:216; found: molpeak (M+H)+:216.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]([N:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH3:19])(=[O:17])[CH3:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N:18]([C:15](=[O:17])[CH3:16])[CH3:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Amino-1-benzylpiperidine (3.63 ml, 17.8 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (4.00 g, 16.2 mmol) prepared in Preparative Example 12 and sodium acetate (2.65 g) in ethanol (40 ml). The obtained mixture was stirred at room temperature for 4 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-(1-benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless viscous oil. This oil was dissolved in 4N aqueous hydrochloric acid and the obtained solution was heated under reflux for 3 hours. The resulting mixture was concentrated to give a solid residue. This residue was recrystallized from ethyl acetate to give the title compound as a white crystal (highly hygroscopic one) (5.80 g, overall yield of two steps: 80%). m.p. (°C.): amorphous (highly hygroscopic)
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([NH2:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([NH2:12])=[O:11])=[CH:15][CH:16]=1
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(Oc1ccc(N)cc1)C(N)=O

Procedure:
2-(4-Nitrophenoxy)-2-methylpropanamide was dissolved in methanol (50 mL) and to the solution was added 10% Pd—C (500 mg). The reaction mixture was reacted under hydrogen atmosphere (˜40 psi) for 1 h. The catalyst was filtered off over celite. The filtrate was evaporated to give 2-(4-aminophenoxy)-2-methylpropanamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][N:37]1[C:43](=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH2:34][N:40]2[CH2:41][CH2:42][C:43](=[O:44])[N:37]([CH3:36])[CH2:38][CH2:39]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C\C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CN1CCNCCC1=O
Product: COc1cc(-c2csc3c(/C=C\CN4CCC(=O)N(C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-(4-{4-amino-7-[(1Z)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl }-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide, 4-methyl-1,4-diazepan-5-one (trifluoroacetic acid salt), and General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.01 (m, 1H), 7.98 (s, 1H), 7.70 (d, 1H), 7.62 (s, 1H), 7.59 (d, 1H), 7.36 (s, 1H), 7.32 (d, 1H), 7.20 (m, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.69 (d, 1H), 6.21 (m, 1H), 5.65 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H); 3.47 (m, 2H), 3.32 (m, 2H), 3.02 (m, 2H), 2.85 (s, 3H), 2.58 (m, 4H); MS: (M−H)− 593.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11](=O)[CH2:12]Br)[O:9][CH:10]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:8]3[O:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1coc(C(=O)CBr)c1
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)O)co3)cs2)cc1OCC

Procedure:
4-Ethoxycarbonyl-2-(α-bromoacetyl)furan and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-furyl)thiazole.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1F.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:24]3[C:23]([Cl:22])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2CN(Cc3ccccc3)CCO2)cc1Cl
Reactant: Fc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cc(C2CN(Cc3ccccc3)CCO2)ccc1Oc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56 mmol), 2,6-dichlorofluorobenzene (0.26 g; 1.56 mmol) and K2CO3 (0.32 g; 2.35 mmol) in DMF (10 mL) was heated at 100° C. for three days. After cooling to RT, the mixture was diluted with EtOAc and washed with water (3×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5) to afford 4-Benzyl-2-[3-chloro-4-(2,6-dichloro-phenoxy)-phenyl]-morpholine (0.35 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=[O:9].C(Cl)(Cl)Cl.O.[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([O:10][CH2:19][CH3:20])=[O:9]
Reactant: O=C(O)COc1cccc(CO)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)COc1cccc(CO)c1
Reaction time: 72 h

Procedure:
A solution of 3-(hydroxymethyl)phenoxyacetic acid (3.18 g.) in ethanol (30 ml.) was treated with concentrated sulphuric acid (10 drops) and allowed to stand for 3 days. Chloroform (100 ml.) and water (50 ml.) were then added. The organic phase was separated, washed sequentially with saturated aqueous sodium hydrogen carbonate solution (2×50 ml.), water (50 ml.) and saturated brine (50 ml.) and then dried (MgSO4) The dried solution was evaporated and the residue purified by flash column chromatography, eluting with petrol (40°-60° )/ ethyl acetate (60:40 v/v) to give ethyl 3-(hydroxymethyl)phenoxyacetate (2.6 g.) as a colourless oil, NMR: 1.25 (3H,t), 2.8 (1H,br s), 4.25 (2H,q), 4.6 (4H,s) and 6.6-7.4 (4H,m)ppm.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[NH:19]2)=[CH:14][CH:13]=1.[CH:26]([CH2:28][C:29](O)=[O:30])=[CH2:27].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[N:19]2[C:29](=[O:30])[CH2:28][CH:26]=[CH2:27])=[CH:16][CH:17]=1
Reactant: C=CCC(=O)O
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Diethyl cyanophosphonate (2.1 mL) was added to a solution of (2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidine (934 mg), vinylacetic acid (1.15 mL), and triethylamine (3.82 mL) in DMF (10 mL), and the reaction solution was stirred at room temperature for six hours. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 744 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>C(Cl)Cl>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][NH:21][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(O)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCC(O)CO)cc1
Reaction time: 2 h

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (Fluka, 1.00 g; 4.51 mmol) in DCM (20 mL) was treated with triethylamine (1.25 ml; 9.02 mmol) and 3-amino-1,2-propanediol (Aldrich, 518 μl; 6.77 mmol). After 2 hours, the organic solvents were evaporated in vacuo, the residue was taken up in EtOAc and extracted with a saturated NH4Cl solution. The combined organic layers were dried over MgSO4 and evaporated to dryness to give the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.FC(F)(F)S(O[Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])(=O)=O>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([O:14][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[CH:4]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:8]=1
Reactant: OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To a stirred solution of (2R)-bis(3,5-bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol ((R)-33, 1.051 g, 2.0 mmol) and triethylamine (TEA, 1.68 mL, 12.0 mmol, 6.0 equiv) in anhydrous methylene chloride (5.0 mL, 78 mmol) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf, 1.41 mL, 6.0 mmol, 3.0 equiv). The resulting reaction mixture was stirred at room temperature for 20 h before being heated at 100° C. for 10-20 h. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-10% EtOAc/hexane gradient elution to give (2R)-2-(bis[3,5-bis(trifluoromethyl)phenyl][tert-butyl(dimethyl)silyl]oxymethyl)pyrrolidine ((R)-36, 1.167 g, 1.279 g theoretical, 91.2% yield) as a very viscous colorless syrup. For (R)-36: 1H NMR (CDCl3, 400 MHz) δ ppm 8.09 (s, 2H), 7.87 (s, 2H), 7.75 (s, 2H), 4.33 (m, 1H), 2.98 (m, 1H), 2.54 (m, 1H), 1.86 (m, 1H), 1.70 (m, 1H), 1.56 (m, 2H), 0.95 (s, 9H), −0.21 (s, 3H), −0.45 (s, 3H); C27H29F12NOSi (MW, 639.59), LCMS (D) m/e 640.4 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([Cl:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[ClH:45].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:42]([C:39]3[CH:38]=[CH:37][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:41][CH:40]=3)(=[O:44])=[O:43])=[C:3]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(N3CCCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1
Product: Cl

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 4-methylsulfonylbenzenesulfonylchloride (69 mg, 0.269 mmole) to give 38 mg as purple solid. M+1 565.3 Calcd 565.12; 1HNMR δ 8.08–7.48 (m, 9H), 6.76 (d, 1H), 6.48 (dd, 1H), 6.32 (d, 1H), 3.61 (app t, 2H), 3.21 (app t, 2H), 3.17 (app t, 2H), 3.14 (app t, 2H), 2.08–2.00 (m, 2H).