Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Cl:11][C:12]([Cl:16])([Cl:15])[C:13]#[N:14]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.[OH-].[K+]>[Cl:11][C:12]([Cl:16])([Cl:15])[C:13](=[NH:14])[O:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: OCc1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: N=C(OCc1ccc(F)cc1F)C(Cl)(Cl)Cl
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Tetrabutyl ammonium hydrogen sulphate (15 mg) was added to 2,4-difluorobenzylalcohol (1.0 g, 6.94 mmol) in CH2Cl2 (10 ml) and KOH (50%, 10 ml). This mixture was cooled to −15° C. prior to the addition of trichloroacetonitrile (1.2 ml, 8.32 mmol). After 30 min at −15° C. and 3 h at ambient temperature the phases were separated. The aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried with MgSO4 and reduced to one third. The residue was filtered through celite and concentrated to give the crude 2,4-difluorobenzyl trichloroacetimidate (1.83 g, 92%) as a yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([O:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:8][CH2:9][C:10]1[N:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([O:26][C:27]([CH3:32])([CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[CH:15][CH:14]=2
Reactant: COC(=O)C(C)(C)Oc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Oc1ccc2c(=O)n(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Methyl 2-[(3-{[(tert-butoxycarbonyl)amino]methyl-}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate (0.16 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give methyl 2-{[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}-2-methylpropanoate hydrochloride(0.10 g, 71.4%) as crystals.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4]1.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH:31]=O)=[CH:29][N:28]=[CH:27]2)=[CH:23][C:22]=1[F:35])#[N:20].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:35][C:22]1[CH:23]=[C:24]([CH2:25][N:26]2[C:30]([CH2:31][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=5)[CH:11]=[CH:10][CH:9]=4)[CH2:4]3)=[CH:29][N:28]=[CH:27]2)[CH:33]=[CH:34][C:21]=1[C:19]#[N:20]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: N[C@@H]1CCN(c2cccc3ccc(O)cc23)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(c3cccc4ccc(O)cc34)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-[7-hydroxynaphthalen-1-yl]pyrrolidine hydrochloride, as described in Step J, (85 mg, 0.32 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described in Example 1, Step G, (75 mg, 0.33 mmol), were stirred in MeOH (1 mL) and N,N-diisopropylethylamine was added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature then NaCNBH3 (26 mg, 0.42 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (1 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (3 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—1% to 6% MeOH—0.1% to 0.6% NH4OH to yield the titled product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].N1CCOCC1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[CH:23][C:24](Cl)=[O:25])[C:20](=[O:27])[O:19]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:24](=[O:25])[CH:23]=[C:21]1[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:22]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: NCc1ccc(F)c(F)c1
Solvent: C1COCCN1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)c(F)c2)O1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a stirred suspension of 3,4-difluorobenzylamine (0.43 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5–4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2Cl2 (3 mL) and the mixture stirred for 1 h. The mixture was filtered and the filtrate concentrated to give the title product as a white solid (81.8 mg, 92% yield). MS calcd for C14H13F2NO4Na (M+Na): 320.29. found: 320.27.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 6.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 339 mg of 4-methylindoline hydrochloride, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 241 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 22 mg of 2-[2-(4-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a fuchsia crystalline powder, the characteristics of which are the following:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:16]([OH:18])=O)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1)=[O:2].[CH3:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[C:5]([C:16]([NH:27][CH2:26][C:23]2[CH:24]=[N:25][C:20]([CH3:19])=[CH:21][CH:22]=2)=[O:18])[CH:6]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1)=[O:2]
Reactant: Cc1ccc(CN)cn1
Reactant: Cc1ccc(-c2cc(C=O)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C=O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Temperature: 60 °C

Procedure:
Into a round bottom flask were combined 5-formyl-4′-methylbiphenyl-3-carboxylic acid (3.00 g, 12.5 mmol), (6-methylpyridin-3-yl)methanamine (1.91 g, 15.6 mmol), N,N-diisopropylethylamine (6.46 g, 49.9 mmol) and N,N-dimethylformamide (97 mL). N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (9.50 g, 25.0 mmol) was added in one portion and the mixture was heated at 60° C. for 2 h. After cooling, the mixture was poured onto saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using methylene chloride:methanol gradient (0-10%) to afford the title compound. LC-MS: 346.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6): 10.14 (s, 1H), 8.46-8.43 (m, 2H), 8.37-8.33 (m, 2H), 7.72 (d, 2H, J=8.0 Hz), 7.64 (dd, 1H, J=8.0 Hz), 7.34 (d, 2H, J=7.9 Hz), 7.22 (d, 2H, J=7.9 Hz), 4.51 (d, 2H, J=5.9 Hz), 2.44 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10]C)[CH:5]=[C:6]([O:8]C)[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cc(O)cc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-1,3-dimethoxybenzene (5.41 g, 31.3 mM) in methylene chloride (75 mL) at −78° C. was stirred with a 1M solution of BBr3 in methylene chloride (63 mL) for 45 minutes. The reaction was allowed to warm to room temperature overnight and diluted with water (75 mL). The layers were separated and the aqueous layer washed two times with methylene chloride. The aqueous layer was acidified with 1N HCl and extracted 3 times with ethyl acetate. The combined organic layers were washed with 1N sodium thiosulfate (1×35 mL) and water (1×25 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure and purified by chromatography (methylene chloride/acetone) to provide the titled compound. MS ESI(−)) m/e 143 (M−H)+; 1H NMR (300 MHz, CDCl3) δ 6.45 (d, 2H), 6.25 (t, 1H), 5.41 (bs, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:24])([CH3:23])[C:9]([NH:11][CH:12]2[CH2:14][CH:13]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.CC(C)([O-])C.[Na+].COC1C=C([C@H]2C[C@@H]2N2C3=NC=CN=C3C(C)(C)C2=O)C=CC=1>C1COCC1>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C@@H:13]2[CH2:14][C@@H:12]2[N:11]2[C:2]3=[N:7][CH:6]=[CH:5][N:4]=[C:3]3[C:8]([CH3:24])([CH3:23])[C:9]2=[O:10])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C2CC2NC(=O)C(C)(C)c2nccnc2Cl)c1
Agent: CC(C)(C)[O-]
Agent: COc1cccc([C@H]2C[C@@H]2N2C(=O)C(C)(C)c3nccnc32)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc([C@@H]2C[C@@H]2N2C(=O)C(C)(C)c3nccnc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of 2-(3-chloropyrazin-2-yl)-N-(2-(3-methoxyphenyl)cyclopropyl)-2-methylpropanamide (0.183 g, 0.529 mmol), sodium tert-butoxide (Aldrich, 0.102 g, 1.058 mmol) in THF was stirred at room temperature overnight. Reaction mixture was directly loaded onto a Biotage samplet. Purification (0-100% EtOAc/hexane) produced mixture of products 5-((1S,2R)-2-(3-methoxyphenyl)cyclopropyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one and 5-((1S,2S)-2-(3-methoxyphenyl)cyclopropyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.111 g, 0.359 mmol, 68% yield). M+1: 310.0. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (d, J=1.90 Hz, 6 H) 1.54-1.63 (m, 1 H) 1.66-1.75 (m, 1 H) 2.62 (ddd, J=9.87, 6.72, 3.58 Hz, 1 H) 2.93-3.06 (m, 1 H) 3.82 (s, 3 H) 6.73-6.83 (m, 1 H) 6.86-6.97 (m, 2 H) 7.16-7.31 (m, 1 H) 8.11 (s, 2 H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[Si:20]([O:27][C:28]1[CH:33]=[C:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:31]=[CH:30][C:29]=1[C@H:42]1[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][N:9]([CH3:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:48][C@H:45]2[CH2:46][CH2:47][C@H:42]([C:29]3[CH:30]=[CH:31][C:32]([O:34][Si:35]([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36])=[CH:33][C:28]=3[O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH2:43][CH2:44]2)=[O:15])=[CH:12][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)O[C@H]2CC[C@H](c3ccc(O[Si](C)(C)C(C)(C)C)cc3O[Si](C)(C)C(C)(C)C)CC2)cc1
Reaction time: 24 h

Procedure:
Triethylamine (20 μl), 4-dimethylaminopyridine (catalytic amount) and 4-dimethylaminobenzoyl chloride (26 mg) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (30 mg) in dry dichloromethane (2 ml) at room temperature under argon. After 24 hr, the solvent was removed under reduced pressure and the residue was partitioned between water (10 ml) and ethyl acetate (20 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were washed with brine (10 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:24 v/v) to give the title compound as a white solid (18 mg, 45%); m/z (ES+) 585 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:45]=[CH:44][C:17]([C:18]([NH:20][C@@H:21]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[CH2:22][N:23]([CH3:36])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[O:19])=[C:16]([F:46])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.SC1C=CC(C(O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]2[CH:45]=[CH:44][C:17]([C:18]([NH:20][C@@H:21]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[CH2:22][NH:23][CH3:36])=[O:19])=[C:16]([F:46])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CN(C[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cccc(Cl)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (2.68 g, 4.01 mmol) in DMF (20 mL) was added 4-mercaptobenzoic acid (1.235 g, 8.01 mmol) and K2CO3 (2.214 g, 16.02 mmol). The reaction mixture was heated at 40° C. overnight under nitrogen. Water (50 mL) was added, and the mixture turned into homogenous. The reaction was stirred at room temperature for 30 min, and then water (150 mL) was added slowly. Light yellow solid was precipitated out. The mixture was stirred for another 30 min, and the suspension was filtered out. The solid was washed well with water, followed by heptane, and air dried for 1 h. The solid was suspended in water and stirred at room temperature for 1 h, and then filtered. To the solid was added EtOAc, and slowly rotated on rotavap to remove excess ethyl acetate until about 20 mL of EtOAc left, the white solid was filtered, and redissolved in acetonitrile and water, lyophilized. The solution was dried on lyophilizer to afford (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (1.31 g, 2.69 mmol, 67.2%). LCMS (m/z): 484.3 (MH+), 0.66 min; 1H NMR (500 MHz, METHANOL-d4) δ ppm 7.90 (s, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.70 (dd, J=1.1, 8.0 Hz, 1H), 7.63 (d, J=10.7 Hz, 1H), 7.48 (s, 1H), 7.38 (d, J=5.4 Hz, 2H), 7.32 (dt, J=1.9, 4.6 Hz, 1H), 5.33 (dd, J=5.2, 9.0 Hz, 1H), 4.05 (dd, J=3.5, 11.0 Hz, 2H), 3.57 (dt, J=1.9, 11.8 Hz, 2H), 3.12-3.04 (m, 1H), 3.04-2.88 (m, 2H), 2.48 (s, 3H), 1.89-1.88 (m, 1H), 1.96-1.76 (m, 4H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.[CH3:28][O:29][C:30]1[CH:42]=[CH:41][C:33]([CH2:34][C@H:35]([CH:38]([CH3:40])[CH3:39])[CH2:36]O)=[CH:32][C:31]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48]>ClCCl>[CH3:28][O:29][C:30]1[CH:42]=[CH:41][C:33]([CH2:34][C@H:35]([CH:38]([CH3:40])[CH3:39])[CH2:36][Br:20])=[CH:32][C:31]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCOc1cc(C[C@@H](CO)C(C)C)ccc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCCOc1cc(C[C@@H](CBr)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
Triphenylphosphine (108.6 g) and, in portions, N-bromosuccinimide (73.7 g) are added in succession at 0° C., with stirring, to a solution of 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butanol (102.2 g) in dichloromethane (2 liters). The batch is stirred for a further 18 hours at room temperature and is then concentrated under reduced pressure. The residue is purified by means of FC on silica gel (ethyl acetate/hexane 1:4). The title compound (102.2 g) is obtained in the form of a white solid: m.p. 52-53° C. (recrystallised from diethyl ether/hexane). Rf (ethyl acetate/hexane 1:1)=0.56. Anal. C17H27BrO3 (359.30): calc. C, 56.83; H, 7.57; Br, 22.24; found C, 56.81; H, 7.34; Br, 22.06.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:17]([NH:16][CH2:15][CH2:14][CH2:13][Cl:12])=[O:18])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NCCCCl
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(NC(=O)NCCCCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of 4-tert-butylaniline (1.0 g, 1.07 mmol) in 5 mL toluene was added 3-chloropropylisocyanate (0.69 mL, 6.70 mmol). The reaction was allowed to stir at ambient temperature for 16 h. The reaction was partitioned between saturated NaHCO3 and ethylacetate. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 1-(4-tert-butylphenyl)-3-(3-chloropropyl)urea (31%). LCMS [M+H]+=269.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10]N)[CH:7]=[CH:8][CH:9]=1.[C:12]1(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)C.C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:13]3[CH2:12][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:10][C:6]=2[CH:5]=1
Reactant: COc1cccc(NN)c1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c3c([nH]c2c1)-c1ccccc1C3
Temperature: 85 °C
Yield: 52.2 %

Procedure:
To a solution of 3-methoxyphenylhydrazine hydrochloride (3.65 g, 20.9 mmol) and 1-indanone (2.77 g, 21.0 mmol) in ethanol (11.8 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Orange precipitate began to form upon cooling, and the mixture was subsequently emerged in an ice water bath to further induce crystallization. The solid was collected by vacuum filtration and dissolved in 22 mL isopropanol. Sulfuric acid (36 N, 1.5 mL) was added via syringe, and the resulting solution was stirred at reflux (90° C.) for 16 hours. Upon cooling to room temperature, the solution was basified to pH 10 with aqueous sodium hydroxide (2% by mass) resulting in the formation of precipitate. The solid was collected by vacuum filtration to yield 29a as an orange solid (2.55 g, 10.9 mmol). Crude product was brought on to the next step without purification. For purposes of characterization, the product was purified by flash column chromatography (20:1 hexanes—ethyl acetate). 1H NMR (600 MHz, CDCl3): δ 8.18 (s, 1H), 7.50-7.52 (m, 2H), 7.40-7.41 (d, 1H, J=7.2 Hz), 7.30-7.32 (t, 1H, J=7.8 Hz), 7.16-7.19 (td, 1H, J=7.8, 1.2 Hz), 6.95 (d, 1H, J=2.4 Hz), 6.83-6.84 (dd, 1H, J=8.4, 2.4 Hz), 3.88 (s, 3H), 3.69 (s, 2H); 13C NMR (150 MHz, CDCl3): δ 156.2, 147.3, 142.3, 141.5, 135.3, 126.5, 125.3, 124.1, 121.9, 119.5, 119.4, 116.7, 109.6, 96.2, 55.7, 30.3. FTIR: cm−1 3399, 1612, 1405, 1255, 1155, 1041, 820. ESI-HRMS: Calcd. for C16H13NO+ [M]+: 235.0992. found 235.0990.
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:16][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2c1CCC2O
Solvent: c1ccccc1
Product: O=C(O)c1cccc2c1CCC2Cl
Reaction time: 3 h

Procedure:
To 30 ml. of benzene is added 5.35 g. of 1-hydroxyindan-4-carboxylic acid. Following the addition of 15 ml. of thionyl chloride, the mixture is stirred fo 3 hours. Then, the reaction mixture is concentrated to dryness under reduced pressure and the resultant crystals are recrystallized from benzene. The described procedure gives 1-chloroindan-4-carboxylic acid melting at 135.5°-137.5°C.
Reaction SMILES: [CH:1]([C:4]1[C:13]([NH2:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C>[CH:1]([C:4]1[C:13]([NH:14][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)c1ccc2cccnc2c1N
Agent: CN(C)c1ccncc1
Product: CC(C)c1ccc2cccnc2c1NS(=O)(=O)c1ccccc1
Yield: 39.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 7-isopropylquinolin-8-amine (Intermediate 62) (150 mg, 0.81 mmol), bezenesulfonyl chloride (170 mg, 1.0 mmol) and DMAP (cat.) gave the title compound (105 mg, 40%) after purification by column chromatography with n-hexane/EtOAc (17:3-4:1) gradient elution.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH:5][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
Mix L-serine methyl ester (6.6 mmol) and pyridine (60 mL). Add, by dropwise addition, benzyl chloroformate (7.3 mmol) and stir overnight. Remove excess pyridine in vacuo and dissolve the residue in a two-phase mixture of ethyl acetate/water. Separate the organic phase and extract the aqueous phase with additional ethyl acetate (2×). Wash the combined organic phases with water, then brine and dry (MgSO4). Evaporate the solvent in vacuo to give N -(benzyloxycarbonyl)-L-serine methyl ester.
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][O:6][C:7](=[O:48])[CH:8]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=2)[CH:31]([CH3:46])[C:30]1=[O:47])[CH2:9][CH2:10][O:11][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:48])[CH:8]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:43])[F:44])[CH:36]=2)[CH:31]([CH3:46])[C:30]1=[O:47])[CH2:9][CH2:10][OH:11]
Reactant: COC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1CCN(c2cccc(OC(F)(F)F)c2)C(C)C1=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(CCO)N1CCN(c2cccc(OC(F)(F)F)c2)C(C)C1=O
Reaction time: 18 h
Yield: 49.4 %

Procedure:
Boron trichloride solution (1 M in CH2Cl2, 1.33 mL, 1.33 mmol) was added at 0° C. to a solution of 4-(tert-butyl-diphenyl-silanyloxy)-2-[3-methyl-2-oxo-4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-butyric acid methyl ester (430 mg, 0.68 mmol) in CH2Cl2 (6 mL), then the ice bath was removed and the solution stirred for 18 h. Another portion of boron trichloride solution (1 M in CH2Cl2, 0.70 mL, 0.70 mmol) was then added, then after 6 h the reaction mixture was partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 4:1) afforded the title compound (131 mg, 42%), which contained 15% of the lactonized side product, 3-methyl-1-(2-oxo-tetrahydro-furan-3-yl)-4-(3-trifluoromethoxy-phenyl)-piperazin-2-one. Light yellow oil, MS: 391.1 (M+H)+.