Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.Cl.[CH2:24]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])[CH3:25].C(N(CC)CC)C.Cl>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:31])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c2c1OC
Temperature: 100 °C
Reaction time: 10 h
Yield: 70.1 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.50 g, 5.39 mmol), β-alanine ethyl ester hydrochloride (2.48 g, 16.1 mmol) and triethylamine (4.50 mL, 32.3 mmol) in anhydrous DMSO (30 mL) was stirred at 100° C. for 10 h. After cooling, the reaction mixture was poured into ice-water (50 mL) and acidified with 1M HCl. The product was extracted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Trituration of the residue with MeOH (30 mL) gave 5-amino-1-cyclopropyl-7-[2-(ethoxycarbonyl)ethylamino]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.54 g, 70%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[CH3:14])#[N:2]>O1CCCC1.CO.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[CH3:14])#[N:2]
Reactant: Cc1cc(/C=C/C(=O)O)ccc1C#N
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)O)ccc1C#N
Reaction time: 8 h
Yield: 99.9 %

Procedure:
5.15 g (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid were dissolved in a mixture of 250 ml tetrahydrofuran and 125 ml methanol. 510 mg palladium on charcoal (10%) were added and the reaction mixture was stirred under a hydrogen atmosphere overnight. The catalyst was filtered off over a celite pad. The solvent was removed in vacuo to obtain 5.2 g 3-(4-Cyano-3-methyl-phenyl)-propionic acid as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:14][C:15]([F:33])([F:32])[C:16]([C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][C@H:24]([C:29](O)=[O:30])[CH2:23][CH2:22][C:21]=2[N:20]=1)([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:29]([CH:24]3[CH2:23][CH2:22][C:21]4[N:20]=[C:19]([C:16]([CH3:18])([CH3:17])[C:15]([F:33])([F:32])[F:14])[CH:28]=[CH:27][C:26]=4[CH2:25]3)=[O:30])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(N)cc21
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCc2ccc(NC(=O)C3CCc4nc(C(C)(C)C(F)(F)F)ccc4C3)cc21
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 64.1 %

Procedure:
To a mixture of 1-acetyl-6-amino-indoline (32 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14 mmol) was added HATU (79 mg, 0.21 mmol) in NMP (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol). After 1.3 h, the reaction was heated to 60° C. After 25 h, the material was filtered and purified by reverse-phase HPLC (40-75% ACN in 0.1% HCO2H/H2O). The fractions were stirred with MP-carbonate resin (1.0 g, 3.0 mmol/g) overnight, filtered and concentrated to afford the amide (40 mg, 64%) as a solid foam. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.21 (d, J=1.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.38 (dd, J=1.8, 8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 4.09 (t, J=8.5 Hz, 2H), 3.08 (t, J=8.5 Hz, 2H), 3.02-2.85 (m, 4H), 2.85-2.74 (m, 1H), 2.18-2.12 (m, 1H), 2.16 (s, 3H), 1.93-1.82 (m, 1H), 1.55 (s, 6H); m/z=446.5 (M+1)+.
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[CH2:3][O:4][C:5]([NH:7][C:8]([NH2:10])=[S:9])=[O:6].[C:13]([NH:16][CH:17]([C:23](=O)[CH2:24]Br)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14].CN(C)C1C=CC=CC=1>C(O)C>[C:13]([NH:16][CH:17]([C:23]1[N:10]=[C:8]([NH:7][C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:11])[Cl:12])=[O:6])[S:9][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])[CH3:14]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CBr
Reactant: NC(=S)NC(=O)OCC(Cl)(Cl)Cl
Solvent: CCO
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)C(NC(C)=O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2.51 g of N-(β,β,β-trichloroethoxycarbonyl)thiourea and 2.66 g. of ethyl α-acetamido-β-oxo-γ-bromobutyrate in 50 ml. of ethanol is added 1.8 g. of N,N-dimethylaniline. The mixture is stirred for 24 hours at room temperature, and condensed under reduced pressure. The residue is dissolved in 30 ml. chloroform and the solution is washed with 3 N-HCl, water, and dried. The solid matter which is obtained by removal of chloroform is purified by silica gel chromatography to give ethyl α-acetamido-2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-ylacetate. 1.43 g. Melting point: 161.9° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)O)=[C:5]([CH3:25])[O:4][N:3]=1.[N:26]1C=CC=CC=1.O=S(Cl)Cl>C1COCC1>[NH2:26][C:10]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:25])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: c1ccncc1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccc(F)cc1)C(=O)N2
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1noc(C)c1-c1ccc2c(c1)C(N)(c1ccc(F)cc1)C(=O)N2
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
Under N2, to a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)-3-hydroxyindolin-2-one (52 g, 154 mmol, 1.0 eq) in THF (500 mL) was added pyridine (40 mL, 496 mmol, 3.2 eq) and SOCl2 (16 mL, 219 mmol, 1.4 eq) slowly at −15° C.˜−20° C., the mixture was stirred for 20 min at −15° C.˜−20° C., quenched with brine, washed with brine (300 mL×2), to the THF layer was added NH3/H2O (100 mL), the mixture was stirred for 2 hours at room temperature, washed with brine, dried, concentrated, purified by silicon gel to give a crude product which was recrystallized from i-PrOH/toluene to give 14 g (yield 27%) product as white solid. 1H NMR (DMSO-d6) δH 10.57 (s, 1H), 7.40-7.44 (m, 2H), 7.22-7.24 (dd, 1H, J=8.0 Hz, 1.6 Hz), 7.11-7.16 (m, 3H), 6.98-7.00 (d, 1H, J=8.0 Hz), 2.75 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: Nc1nccs1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 4) (2.0 g) DIPEA (4-ml) and HATU (3.05 g) were dissolved in DMF (20 ml) and stirred at room temp for 15 min. 2-Aminothiazole (801 mg) was added and the mixture was stirred at room temp for 18 h. The solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml) dried (magnesium sulphate) concentrated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexanelethyl acetate (4: 1) to give the title compound (1.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2F)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC(c4ccccc4F)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)([O-:13])=[O:12]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:10])=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: OCc1cccc(NO)c1
Product: O=[N+]([O-])c1ccccc1C=[N+]([O-])c1cccc(CO)c1
Yield: 64 %

Procedure:
The reaction of hydroxylamine 91 (1.36 g, 10 mmol) with 2-nitrobenzaldehyde (59) (1.51 g, 10 mmol) afforded, after workup, a yellow oil. The crude product was recrystallized from acetone/petroleum ether to obtain 1.74 g (6.4 mmol, 64%) of 94 as a yellow crystalline solid: mp 97°-99° C.; IR (CH2Cl2) 3605, 1570, 1525, 1340, 1155 cm-1 ; 1H NMR (Me2SO-d6) δ 4.60 (d, J=5.6 Hz, 2H), 5.43 (t, J=5.6 Hz, 1H), 7.49-8.74 (m, 9H); 13C NMR (Me2SO-d6) δ 62.82, 119.85, 120.24, 124.84, 125.06, 128.85, 129.54, 129.79, 130.84, 131.28, 133.83, 144.86, 148.44, 148.55. Anal. Calcd for C14H12N2O4 : C, 61.76; H, 4.41. Found: C, 61.85; H, 4.58.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:5]1[N:10]=[C:9](CS([O-])(=O)=O)[CH:8]=[CH:7][N:6]=1)[CH3:4].[CH3:16][N:17]([CH3:27])[S:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:16][N:17]([CH3:27])[S:18]([N:21]1[CH2:26][CH2:25][N:24]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C@H:3]([O:2][CH3:1])[CH3:4])[N:10]=2)[CH2:23][CH2:22]1)(=[O:19])=[O:20]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: CO[C@H](C)c1nccc(CS(=O)(=O)[O-])n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO[C@H](C)c1nccc(N2CCN(S(=O)(=O)N(C)C)CC2)n1
Yield: 59 %

Procedure:
To a solution of (R)-2-(1-methoxyethyl)-pyrimidin-4-yl-methanesulfonate (prepared according to the method of Example 1, Step E, 2.11 g, 9.1 mmol) in tetrahydrofuran (20 mL) was added dimethylsulfamoyl piperazine (prepared according to the method disclosed in U.S. Pat. No. 2,748,129, 1.94 g, 10 mmol) followed by triethylamine (1.4 mL, 10 mmol). The reaction was refluxed for 15 h, and evaporated to an oily residue. This was extracted with ethyl acetate (20 mL) and the extract was washed first with a saturated aqueous solution of sodium bicarbonate and then with water (10 mL). The ethyl acetate extract was dried over sodium sulfate, filtered, and the filtrate was evaporated to a crude product, which was chromatographed over silica gel. Elution with a mixture of 9:1 ethyl acetate and methanol and evaporation of the solvents gave the title compound of Example 1, Step F (1.75 g, 59%); mp, 65-70° C., [α]D+54.4° (c=1, methanol); 1H NMR (CDCl3, 300 MHz) δ1.48(d, 3H), 2.89(s,6H, 3.31(m, 4H), 3.37 (s, 3H), 3.78(m, 4H), 4.34(q, 1H), 6.41(d, 1H), 8.30(d, 1H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:7][C:8]=1[CH2:9][OH:10])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:35])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]I)=[CH:28][C:27]=1[CH3:34].[H-].[Na+].O>CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:10][CH2:9][C:8]2[S:7][C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)=[N:5][C:4]=2[CH:1]([CH3:3])[CH3:2])=[CH:28][C:27]=1[CH3:34]
Reactant: COC(=O)CCc1ccc(CI)cc1C
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(COCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Reaction time: 3.5 h
Yield: 62.2 %

Procedure:
To a mixture of [4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (0.056 g, 0.18 mmol) and 3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methyl ester (0.070 g, 0.22 mol) in DMF (1 mL) is added sodium hydride (60% dispersion, 0.016 g, 0.67 mmol). After 3.5 h, water is added, and the mixture is extracted with EtOAc. The organics are dried with MgSO4 and concentrated. The crude material is purified by flash chromatography to yield the title compound (55 mg, 60%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][CH:7]=[CH:6]1)(=O)C.C[O-].[Na+].CCOC(C)=O>CO>[O:8]1[C@H:9]([CH2:15][OH:16])[C@@H:10]([OH:11])[C@H:5]([OH:4])[CH:6]=[CH:7]1
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reaction time: 0.33 h

Procedure:
The Tri-O-Acetyl-D-Glucal [SM-A](100 g, 367 mmol) is dissolved in dry MeOH [1.5 L], and then NaOMe (110 mmol, 5.95 g) is added into reaction mixture. Within about 20 minutes, TLC (40% EtOAc/60% hexanes & 100% EtOAc) confirmed de-acetylated glucal. The reaction is quenched with 50WX4 cation exchange resin until pH is near 7.0 by pH strip paper. The mixture is filtered and evaporated to dryness under vacuum to yield syrupy glucal intermediate IntA1(59 g). Theoretical yield 100 g×(146/272) 53.7 g TLC IntA1Rf=0.1, SiO2, 100% Ethyl Acetate
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[NH2:15])[NH:11][C:10](=[O:16])[C:9]2([CH3:18])[CH3:17].Cl>>[CH3:17][C:9]1([CH3:18])[C:8]2[C:12](=[CH:13][C:14]3[N:15]=[N:1][NH:5][C:6]=3[CH:7]=2)[NH:11][C:10]1=[O:16]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: CC1(C)C(=O)Nc2cc3nn[nH]c3cc21
Temperature: 25 °C

Procedure:
240 mg. (3.5 mMole) sodium nitrite were added portionwise to a suspension of 570 mg. (3 mMole) 5,6-diamino-3,3-dimethylindolin-2-one in 6 ml. 1N hydrochloric acid, the temperature being maintained between 0° and 5° C. by ice cooling. A red solution is obtained which is heated to 50° to 60° C. for 5 minutes. After cooling to ambient temperature, the crystalline precipitate obtained is filtered off with suction and washed with water. There are obtained 380 mg. of the title compound in the form of red crystals; m.p. 288°-291° C. (decomp.).
Reaction SMILES: C([Li])CCC.[C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[O:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1.[NH4+].[Cl-]>C1COCC1>[C:9]([O:8][C:6](=[O:7])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:24]2([OH:27])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C2(O)CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
THF (50 mL) in an oven-dried 500 mL single neck flask was cooled in −78° C. bath under N2. A solution of n-butyllithium in hexanes (15.4 mL, 2.5 M, 38.6 mmol) was added dropwise via syringe over 10 min. The clear solution was stirred at −78° C. for 30 min. N-Boc-4-bromoaniline (5.00 g, 18.4 mmol), dissolved in 10 mL THF, was added dropwise over 10 min with stirring then stirred a further 30 min at −78° C. Tetrahydro-4H-pyran-4-one (2.02 g, 20.2 mmol) in 5 mL THF added was dropwise over 10 min. After 150 min, the reaction mixture was allowed to warm to RT then added to 200 mL saturated NH4Cl and extracted with ether (3×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over MgSO4. Filtration and concentration provided the crude product that was recrystallized from 70 mL DCM to give the purified product as a white solid (2.29 g, 42%). MS (ESI): mass calcd. for C16H23NO4, 293.3; m/z found, 276.1 [M−H2O+H]+. 1H NMR (500 MHz, CDCl3): 7.46-7.38 (m, 2H), 7.36 (d, J=8.6 Hz, 2H), 6.48 (s, 1H), 3.90 (m, 4H), 2.30-1.98 (m, 2H), 1.68 (d, J=12.1 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.[Br:38][CH2:39][CH2:40]O>ClCCl>[CH3:1][C:2]([CH3:22])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:5][CH2:40][CH2:39][Br:38])=[O:4]
Reactant: OCCBr
Reactant: CCCCCCCCCCCCCCCCC(C)(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC(C)(C)C(=O)OCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
500 mg (1.6 mmol) of 2,2-Dimethyl-octadecanoic acid (Roth, Bruce D. et al., J. Med. Chem. 1992, 35(9), 1609-17) were dissolved in anhydrous dichloromethane (10 ml), and 350 mg (1.8 mmol) of dicyclohexylcarbodiimide (DCC), and 140 μl (2 mmol) of 2-bromoethanol were added thereto, followed by stirring of the mixture at room temperature overnight. The reaction mixture was purified using a silica gel column (elution by hexane-ethyl acetate (7:1) solvent mixture) to obtain 230 mg of 2-(2,2-dimethyloctadecanoyloxy)ethyl bromide to be used below.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>O1CCOCC1>[N:13]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Product: c1ccc2c(CCn3cncn3)c[nH]c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (4.92 g, 22 mmol) and 1,2,4-triazole (3.03 g, 44 mmol) in abs. dioxane (50 ml) was stirred at 80° C. for 24 h. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (50:1). Yield: 0.792 g (Ind-72, 17%), colourless oil
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][C:13](=N)N)=[CH:7][CH:6]=1.BrC[CH2:18][CH2:19][Cl:20]>O>[Cl:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:8]1[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: N=C(N)SCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1ccncc1
Temperature: 83 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (97 cc) is added dropwise, in the course of 15 minutes and whilst keeping the temperature below 14° C., to a solution of 2-(pyrid-4-yl-methyl)-isothiourea dihydrochloride (116.5 g) in distilled water (240 cc). After heating for 20 minutes at 83° C. and then cooling to 12° C., a 10 N aqueous solution of sodium hydroxide (60 cc) and then 1-bromo-3-chloropropane (81.5 g) are added, whilst stirring, and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (430 cc in total); the organic extracts are combined, washed with distilled water (250 cc) and dried over anhydrous sodium sulphate. After filtration, the solution obtained is poured onto neutral silica gel (125 g) contained in a column of diameter 3.2 cm; the column is then eluted with methylene chloride (1600 cc). The first fraction (400 cc) is discarded; the second fraction (1200 cc) is collected and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. Pyrid-4-yl-methyl 3-chloropropyl sulphide (81 g) is thus obtained in the form of a brown oil.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:11][N:10]=1.[F:22][C:23]([F:41])([F:40])[O:24][C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>O>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][C:12]1[CH:13]=[CH:14][C:9]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][O:29][C:28]3[CH:38]=[CH:39][C:25]([O:24][C:23]([F:22])([F:40])[F:41])=[CH:26][CH:27]=3)[CH2:33][CH2:34]2)=[N:10][CH:11]=1
Reactant: Brc1ccc(OC2CCCCO2)cn1
Reactant: FC(F)(F)Oc1ccc(OCCC2CCNCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)Oc1ccc(OCCC2CCN(c3ccc(OC4CCCCO4)cn3)CC2)cc1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
Toluene (15 ml) was added to a mixture of 2-bromo-5-(tetrahydropyran-2-yloxy)pyridine (2.58 g, 10 mmol), 4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine (3.18 g, 11 mmol) and sodium tert-butoxide (1.35 g, 14 mmol), and then the atmosphere was replaced with nitrogen. Bis(dibenzylideneacetone)palladium (Pd2(dba)3 complex) (0.23 g, 0.25 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthine (xantphos) (0.36 g, 0.63 mmol) were added to the mixture, and the reaction mixture was heated at 100° C. for 3 hours under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The result was purified by silica gel column chromatography (ethyl acetate:hexane=10:90→25:75) to afford the title compound as a pale brown powder (4.45 g, 95%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.CN(C)P(=O)(N(C)C)N(C)C.C([C:29]([O:31][CH2:32][CH3:33])=[O:30])#N>O1CCCC1>[O:15]=[C:12]1[CH2:13][CH2:14][O:9][CH2:10][CH:11]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1COCCC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (1.14 mol/l solution in n-hexane/tetrahydrofuran, 2.5 ml) was added dropwise to a solution of tetrahydro-4H-pyran-4-one (260 mg) in tetrahydrofuran (13 ml) at −78° C., and the mixture was stirred for one hour while warming to 0° C. The reaction solution was cooled to −78° C. again, hexamethylphosphoric triamide (452 μl) was added and subsequently ethyl cyanoformate (280 μl) was added at the same temperature. The mixture was stirred over one hour while warming to 0° C. The reaction solution was separated by adding distilled water and ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (210 mg).