Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[Br:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][O:15][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])=[CH:5][C:4]=1[Cl:14]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
First, 10.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 14.0 g of 1,3-dibromopropane, and 50 ml of N,N-dimethylformamide were placed in a reaction vessel, to which 5.3 g of potassium carbonate was added. After stirring at room temperature for 12 hours, the reaction mixture was filtered. The filtrate was poured into diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 6.1 g (yield, 43%) of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene.
Reaction SMILES: [C:1]([NH:8][C:9]1([C:18](O)=O)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OC(C)C)=O.C1(C)C=CC=CC=1.[Br:42][C:43]1[CH:44]=[C:45]([NH2:50])[C:46]([NH2:49])=[CH:47][CH:48]=1.C(O)(=O)C>CN(C)C=O>[Br:42][C:43]1[CH:48]=[CH:47][C:46]2[NH:49][C:18]([C:9]3([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)=[N:50][C:45]=2[CH:44]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)Cc2ccccc2C1
Reactant: Nc1ccc(Br)cc1N
Agent: CC(C)OC(=O)Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2nc3cc(Br)ccc3[nH]2)Cc2ccccc2C1
Temperature: -20 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of N-Boc-2-aminoindane-2-carboxylic acid (3.30 g, 11.9 mmol) in N,N-dimethylformamide (15.0 mL) and 4-methylmorpholine (2.20 mL, 20.0 mmol) cooled to −20° C. was added a solution of isopropyl chloroformate in toluene (1.0 M, 20.0 mL, 20.0 mmol) dropwise over one hour. The mixture was stirred for an additional 60 minutes at −20° C. and then 4-bromo-1,2-benzenediamine (3.30 g, 17.6 mmol) was added. The reaction mixture was allowed to warm to room temperature for 18 hours. The solvent was evaporated, redissolved in ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetic acid (20.0 mL, 352 mmol) and heated at 60° C. for 2 hours. After cooling, the solvent was removed in vacuo and then purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (3.05 g, 60%) as a brown solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:43])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:42])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:42])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:43])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.29 mmol) was added to a stirred solution of {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.043 g, 0.074 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.035 g, 84%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s., 1 H) 8.71 (s, 2 H) 8.58 (s, 1 H) 8.34 (d, J=7.82 Hz, 2 H) 8.00 (dd, J=8.60, 6.20 Hz, 1 H) 7.90 (s, 1 H) 7.56 (d, J=7.82 Hz, 2 H) 7.37 (br. t, J=8.80, 8.80 Hz, 1 H) 6.64 (d, J=10.27 Hz, 1 H) 3.83 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C27H16F7O4S [(M−H)−] 569, obsd. 569.0.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:29])[C:18]3[C:13](=[CH:14][C:15]([O:30]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:28][O:27][C:24]1[N:25]=[CH:26][C:21]([C:20]2[CH:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:6][CH:7]=3)[O:12][C:13]3[C:18]([C:19]=2[CH3:29])=[CH:17][CH:16]=[C:15]([OH:30])[CH:14]=3)=[CH:22][CH:23]=1
Reactant: C1CCNC1
Reactant: COc1ccc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)cn1
Product: COc1ccc(C2=C(C)c3ccc(O)cc3OC2c2ccc(OCCN3CCCC3)cc2)cn1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2-methoxy-pyridine and pyrolidine as the starting material.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:5]([CH2:12][CH:13]=[CH2:14])=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.Cl[CH:16]([F:18])[F:17].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:17][CH:16]([O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[C:5]=1[CH2:12][CH:13]=[CH2:14])[F:18]
Reactant: FC(F)Cl
Reactant: C=CCc1c(C)cc(C)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCc1c(C)cc(C)cc1OC(F)F
Temperature: 90 °C

Procedure:
125 g of 45% strength sodium hydroxide solution and 10 g of tetrabutyl-ammonium bromide were metered into 100 g of 3,5-dimethyl-2-(2-propen-1-yl)-phenol (C) in 700 ml of toluene. The mixture was heated to 90° C., and 110 g of chlorodifluoromethane were subsequently passed in. After the mixture had cooled to room temperature, 300 ml of water were added, and the toluene phase was separated off. The aqueous phase was extracted twice using 200 ml of tert-butyl methyl ether, and the combined organic phases were dried over sodium sulphate. The mixture was concentrated, and, after distillation, 58.5 g (45% of theory) of 3,5-dimethyl-2-(2-propen-1-yl)-phenyl difluoromethyl ether of a boiling point of 55-65° C. at 0.15 mbar were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[OH:25][CH2:26][CH2:27][NH2:28]>>[OH:25][CH2:26][CH2:27][NH:28][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1
Reactant: NCCO
Reactant: O=S1CCN(c2nc(Cl)nc3c(N4CCCCC4)ncnc23)CC1
Product: O=S1CCN(c2nc(NCCO)nc3c(N4CCCCC4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 3 from 2-chloro-4-(1-oxido-thiomorpholino)-8-piperidinopyrimido[5,4-d]pyrimidine (melting point: 203°-204° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1B(O)O.Cl[C:13]1[C:21]2[C:16](=[CH:17][N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[CH:20]=2)[N:15](C2CCCCO2)[N:14]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:13]1[C:21]2[C:16](=[CH:17][N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[CH:20]=2)[NH:15][N:14]=1
Reactant: Cn1cc(-c2cc3c(Cl)nn(C4CCCCO4)c3cn2)cn1
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: Cc1ccc(F)c(-c2n[nH]c3cnc(-c4cnn(C)c4)cc23)c1
Yield: 21.3 %

Procedure:
Following the procedures in Example 172, 2-fluoro-5-methylphenylboronic acid and 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and deprotected to give 205 as a white solid (21.3% over two steps). 1H NMR (400 MHz, DMSO) 6 (400 MHz, DMSO) δ 13.86 (s, 1H), 9.05 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.88 (d, J=2.7 Hz, 1H), 7.63 (d, J=6.3 Hz, 1H), 7.36-7.27 (m, 2H), 3.88 (s, 3H), 2.40 (s, 3H). LC/MS: m/z 308.0 [M+1]
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[CH:21][N:22]=4)[CH:19]=3)=[CH:12][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=2)=[CH:5][CH:4]=1.[ClH:48]>C(O)C>[ClH:48].[ClH:48].[ClH:48].[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[N:18]2[CH:19]=[C:14]([C:13]3[C:9]([C:6]4[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=4)=[N:10][NH:11][CH:12]=3)[CH:15]=[CH:16][C:17]2=[N:22][CH:21]=1
Reactant: COc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cn1
Agent: Cl
Solvent: CCO
Product: O=c1ccc(-c2n[nH]cc2-c2ccc3ncc(-c4ccccn4)n3c2)c[nH]1

Procedure:
A mixture of 126 mg 6-[3-(6-methoxypyridin-3-yl)-1-trityl-1H-pyrazol-4-yl]-3-(pyridin-2-yl)imidazo[1,2-a]pyridine (compound in Example 363), 5 mL of 5 N hydrochloric acid and 5 mL ethanol was heated overnight under reflux. The reaction solution was evaporated, and the residue was subjected to azeotropic distillation with toluene. The residue was triturated with methanol and ethyl acetate. The crystals were collected by filtration and then dried under reduced pressure with a vacuum pump, to give 66 mg of the title compound as white crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F>C1COCC1.C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccc3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
A slurry of 334 mg (374 mg of 60% in oil, 9.35 mmol) of sodium hydride in 5 mL THF was treated with a solution of 1.0 g (8.5 mmol) of indole in 5 mL THF, followed by stirring at ambient temperature for 15 min. The solution was then treated with 1.35 g (8.5 mmol) of 3,4-difluoronitrobenzene. The solution was stirred at ambient temperature for 48 h, followed by concentration in vacuo to afford brown oil which was dissolved in ethyl acetate and washed with water. Drying (Na2SO4) and concentration in vacuo afforded an oil which was chromatographed over 100 g of 230-400 mesh silica gel, eluting with 20% (v/v) ethyl acetate in hexane. These procedures afforded 1.1 g (51%) of the title compound as a yellow solid. 1H NMR (CDCl3): δ 8.23, 7.74, 7.40, 7.35, 7.30, 6.80.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[CH3:16][Mg]Br>CCOCC>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:16])([OH:13])[C:7]([CH3:11])([CH3:12])[S:8](=[O:9])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CC1(C)C(=O)c2ccc(Br)cc2S1(=O)=O
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC1(O)c2ccc(Br)cc2S(=O)(=O)C1(C)C
Temperature: 25 °C
Yield: 97 %

Procedure:
A cooled (0° C.) solution of 6-bromo-2,2-dimethyl-1-benzothiophen-3(2H)-one 1,1-dioxide (Intermediate 241; 750 mg; 2.59 mmol) in anhydrous Et2O (22.5 ml) was treated carefully with a 3 M solution of methylmagnesium bromide in Et2O (2.6 ml; 7.8 mmol). The white solution was stirred at RT for 1.5 before being quenched with a saturated solution of NH4Cl in water. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to dryness to afford the title compound as a white solid (767 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:32]([C:35]1[C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37][C:36]=1[O:43][C:44]1[CH:45]=[C:46]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:47]#[N:48])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:37]2[C:36]([O:43][C:44]3[CH:45]=[C:46]([CH:49]=[C:50]([CH3:52])[CH:51]=3)[C:47]#[N:48])=[C:35]([CH:32]([CH3:33])[CH3:34])[C:40](=[O:41])[NH:39][C:38]2=[O:42])[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1ccc(CNc2cc(CO)cc(Cl)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Reaction time: 1.5 h
Yield: 44.7 %

Procedure:
To a stirred solution of 2-chloro-6-(p-methoxybenzylamino)-4-pyridinemethanol (278 mg, 1 mmol) in chloroform (10 ml) at 0° C. (ice bath), was added triethylamine (210 μl, 1.5 mmol) and methanesulfonyl chloride (90 μl, 1.2 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo and mixed with (12) (285 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), lithium iodide (134 mg, 1 mmol). Anhydrous DMF (5 ml) was then added into the mixture and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and the filtrate was evaporated in vacuo to give a pale yellow foam. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 244 mg (45%) of a white solid; 1H NMR (200 MHz, CD3OD/CDCl3) δ 1.10 (6H, d, J=7.0 Hz), 2.32 (3H, s), 2.62 (1H, m), 3.81 (3H, s), 4.31 (2H, s), 4.71 (2H, s), 5.98 (1H, s), 6.24 (1H, s), 6.76 (1H, s), 6.87-6.91 (3H, m), 7.18-7.28 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](ON1C(=O)CCC1=O)([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29].C([O-])(O)=O.[Na+].Cl>O1CCOCC1.O>[C:28]([NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][C:12]1[CH:19]=[CH:20][C:9]([CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:10][CH:11]=1)([O:30][CH2:31][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:29]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C[C@H](N)C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine (818 mg, 2.16 mmol), Fmoc-OSu (727 mg, 2.16 mmol) and NaHCO3 (906 mg, 10.8 mmol, 5 equivalents) in 48 ml of dioxane-water (1:1) was stirred at room temperature overnight. The reaction mixture was then cooled to 0° C. and acidified with 180 ml of 0.2 M HCl. The reaction product was extracted with ethyl acetate (30 ml×3), and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (CDCl3-EtOAc-MeOH) to provide N-Fmoc-4-(di-tert-butoxycarbonyl-methyl)-L-phenylalanine as a white solid (650 mg, 50.7%). 1H NMR (DCMSO) δ: 12.704 (1H, s, br), 7.786 (2H, d, J=7.32 Hz), 7.760 (1H, d, J=8.54 Hz), 7.658 (2H, t, J=7.81 Hz), 7.435˜7.200 (4H, m) 7.254 (4H, s), 4.586 (1H, s), 4.274˜4.081 (4H, m), 3.111˜3.040 (1H, dd, J=4.40, 13.67 Hz), 2.913˜2.815 (1H, dd, J=10.75, 13.92 Hz), 1.390 (1H, s), 1.380 (1H, s). FABMS (+Ve), m/z 602 [MH+], 546 [MH+—C4H8], 490 [MH+—2 C4H8]. Anal. calcd. for C20H29NO6: C, 66.90; H, 6.5; N, 2.3. Found: C, 90.40; H, 6.67; N, 2.24.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na+].[I-:15]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCCCCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCCc1ccccc1
Yield: 98.2 %

Procedure:
6-Bromo-1-phenylhexane (18.02 g, 0.075 mol) was dissolved in acetone (300 ml), NaI (44.85 g, 0.299 mol) was added, and the mixture heated at reflux temperature for 18 hours. This was filtered and the acetone evaporated under reduced pressure to give a residual mass which was extracted with n-pentane (150 ml). The insoluble solid was filtered off and the filtrate evaporated to give 6-iodo-1-phenylhexane as a colourless liquid (21.22 g, 99%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:6]=1[NH:29][S:30]([C:33]1[CH:38]=[C:37]([N+:39]([O-])=O)[CH:36]=[CH:35][C:34]=1[N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)(=[O:32])=[O:31])(=[O:3])[CH3:2].[Cl-].[NH4+].O.C(O)(=O)C>C(O)(C)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:6]=1[NH:29][S:30]([C:33]1[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:34]=1[N:42]1[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1)(=[O:31])=[O:32])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)c(OC(C)=O)cc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc(N)ccc2N2CCOCC2)c(OC(C)=O)cc1C

Procedure:
19.5 g (0.029 mol) of the compound obtained in Step (c) above, reduced iron (5.3 g), triirontetraoxide (2.7 g) and ammonium chloride (0.4 g) were suspended in isopropanol (300 ml). To the mixture, a mixed solution of water (40 ml) and acetic acid (2 ml) was added dropwise while refluxing with heating. After the completion of the addition, the mixture was refluxed wih heating for 2 hours and the insoluble materials were removed by filtration while hot. The filtrate was added to water (300 ml) and the crystals thus-precipitated were collected by filtration. Yield: 16.4 g (86%). Melting Point: 110°-112° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][CH2:2][C:3]2([NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])[CH2:4][CH2:5]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(NC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 1-(hydroxymethyl)cyclopropylcarbamate (290 g, 1.55 mol) in DCM (2900 mL) was added DMAP (227 g, 1.86 mol) followed by 4-methylbenzene-1-sulfonyl chloride (323 g, 1.69 mol) in several batches at 10° C. After 2 hours, the reaction mixture was washed with water (2×1000 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford {1-[(tert-butoxycarbonyl)amino]cyclopropyl}methyl 4-methylbenzenesulfonate. The material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(Br)c3)c2)CC1
Yield: 31.9 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-bromobenzoyl chloride (91 μl, 0.687 mmol), 29.3 mg (32%) of the title compound were recovered.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5])#[N:2].CC(O/N=C(/C(NCC=O)=O)\C1N=C(N)SC=1)(C(O)=O)C.C(CC(O)=O)#N.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:56]([Si:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][C:70]([CH2:73]I)=[CH:69][CH:68]=1)([CH3:62])[CH3:61])([CH3:59])([CH3:58])[CH3:57]>C1COCC1>[Si:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]([CH2:73][CH:3]([C:1]#[N:2])[C:4]([N:6]([CH:16]2[CH2:17][CH2:18]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[O:5])=[CH:71][CH:72]=1)([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:62])[CH3:61]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(CI)cc1
Reactant: N#CCC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Agent: CC(C)(O/N=C(/C(=O)NCC=O)c1csc(N)n1)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#CCC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(CC(C#N)C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)cc1
Temperature: 25 °C

Procedure:
2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)acetamide (1 eq.), prepared from Amine 2 and cyanoacetic acid as detailed in Step 1 of Example 1, was dissolved in THF (0.1 M). At −78° C., potassium bis(trimethylsilyl)amide (15% w/w toluene solution, 1 eq.) was then added and the resulting yellow suspension was stirred at −78° C. for 15 min and at −40° C. for 15 min. tert-Butyl{3-[4-(iodomethyl)phenyl]propoxy}dimethylsilane from the previous step (1 eq.) was then added, at −78° C., as a 0.33 M THF solution over a period of 10 min. The resulting pale yellow mixture was allowed to warm slowly to RT over 5 h. The reaction was quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with H2O and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a viscous yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO2, 10:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.