Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C:3]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([OH:5])=[O:4].[CH:28]1(O)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:1].[CH:28]1([O:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:5])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1
Reactant: OC1CCCC1
Agent: Cl
Product: O=C(COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1)OC1CCCC1

Procedure:
Prepared from 1-(4-carboxymethyloxyphenyl)-4-[2-(piperidin-4-yl)ethyl]piperazine dihydrochloride and cyclopentanol.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:3]1=[O:34]>C1COCC1>[O:34]=[C:3]1[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:5]2=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:9]=[C:10]2[CH2:2]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(Br)(Br)C(=O)N3CCCCCCC(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)C3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-(7,7-Dibromo-6-oxo-2,3-di-p-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid (mixture from step 1) (127 mg, 0.211 mmol) in dry THF (5 ml) under nitrogen was treated with 10% Pd(C) (22.48 mg, 0.021 mmol) and the mixture was stirred at RT under an atmosphere of hydrogen for 16 hours. The resulting mixture was filtered through Celite® and washed through with DCM. The filtrate was concentrated under reduced pressure and purification was carried out by chromatography on silica eluting with 0-100% EtOAc in iso-hexane. Further purification was carried out by dissolving the product in DCM (minimal) and loading onto a 20 cm×20 cm preparative TLC plate. The plate was run using a solvent system of 75% EtOAc in iso-hexane (300 ml) and the appropriate strip of Si was scrapped off the plate. The silica was suspended in 10% MeOH/DCM and sonicated. The suspension was filtered, rinsing the solid with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.Cl[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][NH:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1
Reactant: COC(=O)CCl
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(CC=C)c1nc(NCC(=O)OC)n2oc(=O)nc2n1
Reaction time: 21 h

Procedure:
3.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are dissolved in 100 ml of acetone and treated with 4 ml. of methyl chloroacetate and 4 g. of potassium carbonate. The mixture is vigorously stirred for 21 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride and water and extracted twice with methylene chloride. The combined organic extracts are dried over potassium carbonate and evaporated under reduced pressure. The crude product is chromatographed over silica gel using a mixture of methylene chloride and methanol (99:1) for the elution, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}glycine methyl ester which is recrystallized from acetone and petroleum ether; melting point 173°-174° C.
Reaction SMILES: [Li]C(C)(C)C.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10](I)=[CH:9][N:8]=1.Cl([O-])(=O)(=O)=O.[CH2:20]1[C:27]2[CH2:26][CH2:25][CH2:24][N+:23]=2[CH2:22][CH2:21]1.Cl>CCCCC.CCOCC>[Cl:13][C:12]1[CH:11]=[C:10]([C:27]23[CH2:26][CH2:25][CH2:24][N:23]2[CH2:22][CH2:21][CH2:20]3)[CH:9]=[N:8][C:7]=1[Cl:6]
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Clc1cc(I)cnc1Cl
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: Clc1cc(C23CCCN2CCC3)cnc1Cl
Temperature: -20 °C
Reaction time: 0.03 h
Yield: 54.3 %

Procedure:
A solution of 1.7M tBuLi (4.7 mL, 8.0 mmol) in pentane was added to 2,3-dichloro-5-iodopyridine (from step 8a, 1.0 g, 3.65 mmol) in Et2O (15 mL) precooled to -100° C. After stirring for 2 minutes, 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.5 g, 7.3 mmol) was added, and the reaction mixture was allowed to stir for 20 minutes at -100° C. then gradually warm to -20° C. A solution of 2N HCl was added, and the cold bath was removed. After warming to ambient temperature, the reaction mixture was poured over EtOAc and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 phases were combined, dried (MgSO4), concentrated and the residue was chromatographed (silica gel; CHCl3 /MeOH, 99.5:0.5) to afford a light yellow oil (510 mg, 54%). MS (CI/NH3) m/e: 257 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.59-1.71 (m, 2H), 1.80-2.08 (m, 6H), 2.64-2.72 (m, 2H), 3.11-3.20 (m, 2H), 7.99 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH2:9][OH:10])[CH2:5][CH:6]([CH3:8])[CH3:7].[C:11](#N)C.CI>C1COCC1>[CH2:5]([C@H:4]([NH2:3])[CH2:9][O:10][CH3:11])[CH:6]([CH3:8])[CH3:7]
Reactant: CC#N
Reactant: CC(C)C[C@H](N)CO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H](N)CC(C)C
Temperature: 55 °C

Procedure:
Sodium hydride (60% dispersion in oil: 9.39 g, 0.24 mol) was added to a stirred solution of L-leucinol (25 ml, 0.20 mol) in a mixture of dry acetonitrile (12 ml) and dry THF (60 ml) at room temperature under argon. The mixture was heated at reflux for 2 h, cooled to 55° C. and methyl iodide (12.8 ml, 2.1 mol) carefully added. The reaction mixture was heated at reflux overnight and allowed to cool to room temperature. Ice cold brine (100 ml) was added carefully and the mixture extracted with ethyl acetate (3×100 ml) The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was distilled under reduced pressure to give (S)-1-isobutyl-2-methoxyethylamine as a colourless oil which was used directly in the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[N:9]=[C:10](N)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].[OH-].[K+].[Cl:15][CH2:16]C(OC)(OC)OC>COCCO.O>[Cl:15][CH2:16][C:10]1[S:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=2[N:9]=1
Reactant: CCc1cccc2sc(N)nc12
Reactant: COC(CCl)(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CCc1cccc2sc(CCl)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
(Method J) A solution of 4-ethyl-1,3-benzothiazol-2-amine (1.0 g, 5.6 mmol, 1 equiv.) and KOH (7.4 g, 112.2 mmol, 20 equiv.) in 2-methoxy-ethanol (9 ml) and H2O (9 ml), was stirred under N2 and under reflux, for 20 h. After cooling at r.t., the mixture was poured into water (150 ml) and extracted with CH2Cl2 (2×40 ml). The aqueous phase was neutralised with conc. HCl and extracted again with CH2Cl2 (3×70 ml). The combined neutral extracts were washed with water (2×60 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The yellow-green semi-solid residue (790 mg) was mixed with 2-chloro-1,1,1-trimethoxy ethane (1.62 g, 10.4 mmol) and the mixture was stirred, under N2, at 60° C., for 4 h. Volatiles were removed by evaporation under reduced pressure and the brown liquid residue was purified by column chromatography on silica, eluted with CH2Cl2/hexane (10% and 50%), to give a yellow liquid (406 mg, 34% yield over two steps). HPLC-MS (method 1): m/z 212 [M+H]+, Rt=5.00 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)([CH3:4])([CH3:3])[CH3:2].C([N:30]=[C:31]=[S:32])(=O)C1C=CC=CC=1>CC(C)=O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:31]([NH2:30])=[S:32])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1-n1cccn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc(NC(N)=S)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of the compound (1.0 g) obtained in Example 2b and acetone (30 ml), benzoyl isothiocyanate (0.52 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated at reduced pressure. Methanol (50 ml) and potassium carbonate (0.53 g) were added to the resulting residue. The reaction mixture was stirred at room temperature for 80 minutes and then concentrated at reduced pressure. Water was added to the resulting residue and extraction with ethyl acetate was conducted. The organic layer was washed with brine, dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=3:1) to give the titled compound quantitatively.
Reaction SMILES: [H-].[Na+].C[N:4]([CH:6]=O)[CH3:5].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18].[OH2:21]>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17]([N:4]1[C:5]2[CH:10]=[CH:11][CH:12]=[C:13]([CH:16]=[O:21])[C:14]=2[CH:15]=[CH:6]1)(=[O:19])=[O:18]
Reactant: O
Reactant: CN(C)C=O
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reaction time: 0.25 h

Procedure:
To a slurry of sodium hydride (165 mg, 6.9 mmol) in DMF (5 ml) indole-4-carboxaldehyde (500 mg, 3.4 mmol) was added. The mixture was stirred for 15 min and then the 2-methoxy-5-methyl-benzenesulfonyl chloride (1140 mg, 5.2 mmol) was added and the mixture was stirred for 1 h at room temperature. Water was added and the reaction mixture was extracted with EtOAc. Evaporation gave 1.2 g. MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.
Reaction SMILES: N([CH:4](OC)[O:5]C)(C)C.[CH3:9][C:10]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=1[O:24][CH3:25]>CC(N(C)C)=O.C(Cl)(Cl)Cl>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:10]=1[CH2:9][CH:4]=[O:5])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(OC)c(C)c([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(OC)c(CC=O)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
13.3 ml of Me2NCH(OMe)2 was added to a solution of 4.78 g of ethyl 4-methyl-3-(methoxy)-5-nitrobenzoate in 10 ml of dimethylacetamide and the mixture was heated at 80° C. in a sealed tube for 40 minutes. The mixture was diluted with CHCl3, washed with water, dried over Na2SO4, and concentrated. The residue was purified on SiO2 column chromatography to give 4.02 g of the intended compound as a pale tan solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1N
Reactant: Nc1nc(Cl)c2ccccc2n1
Solvent: CCO
Product: Cc1ccccc1Nc1nc(N)nc2ccccc12
Yield: 61 %

Procedure:
2-Amino-4-chloroquinazoline (0.64 g, 0.0036 mol) was heated to 170° in o-toluidine (1 ml, 0.008 mol) for 1 hour. The reaction mixture was dissolved in ethanol, stripped and partitioned between chloroform and NaOH solution (pH 9). The organic solution was dried, filtered and excess solvent removed to give an oil which afforded crystals of 2-amino-4-(2-methylphenylamino)-quinazoline (0.55 g, 62%) m.p. 273°-275° (from ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([S:16][CH3:17])[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.C.[O:19]1CCOCC1>O>[CH3:17][S:16][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH:1]=[O:19])[CH:15]=1
Reactant: C1COCCO1
Reactant: CSc1cc(C)nc2c1ccc1cccnc12
Solvent: O
Product: CSc1cc(C=O)nc2c1ccc1cccnc12
Yield: 41 %

Procedure:
A solution of SeO2 (2.18 g, 19.6 mmol) in a mixture of dioxane (100 mL) and water (4 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 2-methyl-4-methylsulfanyl-[1,10]phenanthroline (1.89 g, 7.90 mmol) in hot dioxane (100 mL) was added through an addition funnel over a period of 1 hour and the reaction mixture was refluxed for additional 45 minutes. The reaction mixture was filtered while hot and the residue rinsed with more hot dioxane (20 mL) and filtered. The filtrate was concentrated in vacuo and the residue obtained was redissolved in hot water, stirred with decolorizing charcoal and filtered. The filtrate was allowed to reach room temperature and basified with saturated NaHCO3 until precipitation of a white solid, which was filtered, washed with cold water and dried in vacuo. A white solid (0.80 g, 41% yield) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]([CH3:37])=[C:14]([N:18]([CH2:22][C:23]2[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=2)[CH2:19][CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:22][C:23]3[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=3)[CH2:19][CH2:20][CH3:21])[C:13]=2[CH3:37])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(Cl)cc2)c1C

Procedure:
Prepared from 4-chlorophenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described Example 25.
Reaction SMILES: [CH:1]12[CH:7]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH2:12](OCC)C.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][CH:7]1[CH:4]2[CH2:3][CH2:2][CH:1]1[CH2:6][CH2:5]2
Reactant: O=C(O)CC1C2CCC1CC2
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask was placed bicyclo[2.2.1]hept-7-yl-acetic acid (554 mg, 3.95 mmol), diethyl ether (20 mL) and methanol (5 mL) and cooled to 0° C. in an ice bath. The mixture was then treated with a 2M solution of (trimethylsilyl)diazomethane in diethyl ether (3.95 mL, 7.9 mmol) dropwise. After the addition was complete, the mixture was warmed to 25° C. and stirred for 1 h. The mixture was concentrated in vacuo to afford bicyclo[2.2.1]hept-7-yl-acetic acid methyl ester (theoretical yield 3.95 mmol) which was used on crude. Bicyclo[2.2.1]hept-7-yl-acetic acid methyl ester (3.95 mmol) in diethyl ether (10 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (224 mg, 5.9 mmol) in diethyl ether (20 mL) cooled to 0° C. The mixture was stirred for an additional 3 h at 0° C. and quenched with a saturated sodium sulfate solution (15 mL), extracted with diethyl ether (3×20 mL). The combined organics were dried over sodium sulfate, concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (12 g column, 20% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) to afford bicyclo[2.2.1]hept-7-yl-methanol (180 mg, 36%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].[CH3:5][N:6]([C@@H:8]1[C:26](=[O:27])[C:25]([C:28]([NH2:30])=[O:29])=[C:24]([OH:31])[C@:23]2([OH:32])[C@H:9]1[CH2:10][C@H:11]1[C:20]([C:21]2=[O:22])=[C:19]([OH:33])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][C:17]=2[OH:34])[CH2:12]1)[CH3:7].[CH2:36]1[CH2:40]OC[CH2:37]1>>[CH:37]1([C:14]2[CH:15]=[CH:16][C:17]([OH:34])=[C:18]3[C:13]=2[CH2:12][C@@H:11]2[C:20]([C:19]3=[O:33])=[C:21]([OH:22])[C@@:23]3([OH:32])[C@H:9]([C@H:8]([N:6]([CH3:7])[CH3:5])[C:26]([OH:27])=[C:25]([C:28]([NH2:30])=[O:29])[C:24]3=[O:31])[CH2:10]2)[CH2:36][CH2:40]1
Reactant: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(I)c4C[C@H]3C[C@@H]12
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [In+3]
Product: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)ccc(C5CC5)c4C[C@H]3C[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A 1000 mL 2 or 3 neck round-bottomed flask with reflux condenser was charged with anhydrous InCl3 (12.1 g, 40.5 mmol) and dried under vacuum with a heat gun. After the flask cooled to ambient temperature and was flushed with argon, anhydrous THF (240 mL) was added. The solution was cooled to −78° C. and c-PrMgBr (244 mL, 122 mmol) as a 0.5 M solution in THF was added. After 15 minutes, the solution was allowed to slowly warm to room temperature to form a clear heterogeneous solution. To the reaction flask was added 7-iodosancycline (19.4 g, 36.0 mmol) and Pd(t-Bu3)2 (0.920 g, 1.80 mmol). The solution was heated to reflux under argon until complete (approximately 1 hour). After cooling to ambient temperature, the solution was quenched with MeOH (1 mL) and poured into a stirring cold solution of 1M HCl (3 L). After 1 hour, the solution was filtered through a pad of Celite, while rinsing with water. The water solution was loaded onto a DVB column for solid phase extraction and the product was isolated by eluting with 1% TFA/CH3CN. The crude product was further purified by preparatory HPLC (C18, linear gradient 20-60% acetonitrile in water with 0.1% TFA, to afford 11.8 g in 72% yield as a yellow solid. 1H NMR (CD3OD) δ 7.18 (d, J=7.4 Hz, 1H), 6.61 (d, J=7.4 Hz, 1H), 3.99 (s, 1H), 3.34 (dd, J=9.1, 2.8 Hz, 1H), 3.05-2.84 (m, 10H), 2.32-2.09 (m, 2H), 0.86-0.75 (m, 2H), 0.51-0.37 (m, 2H). LC/MS (MH+) 455.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)=[C:4]([OH:7])[NH:5][N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:24]([CH3:35])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:25](=[O:26])[CH:24]([O:7][C:4]1[NH:5][N:6]=[C:2]([CH3:1])[C:3]=1[N:8]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[N:9]1)[CH3:35]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1n[nH]c(O)c1-n1ccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c(OC(C)C(=O)c2ccc(Cl)cc2Cl)c1-n1ccc(C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5′-methyl-3-trifluoromethyl-2′H-[1,4′]bipyrazolyl-3′-ol (Intermediate KA)(270 mg, 1.163 mmol) and cesium carbonate (379 mg, 1.163 mmol) in DMF (2.684 ml) at 50° C. is added 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (328 mg, 1.163 mmol) slowly in DMF (1.789 ml). The reaction is stirred at 50° C. for 1 hour before cooling to RT. 2M Na2CO3 (100 ml) is added and the crude product is extracted with EtOAc (2×100 ml). The organic phases are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 24 g SiO2 column to give the title compound as a light brown oil; MS: m/z 433.24 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([F:10])=[CH:4][N:3]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].N1CCCCC1>C(O)C>[F:10][C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:1][C:11](=[O:18])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ncc(F)cc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(F)cnc2[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-amino-5-fluoropyridine-3-carboxaldehyde (2.80 g), diethyl malonate (6.40 g) and piperidine (0.85 g) in ethanol (50 ml) were heated to reflux with stirring for 18 hours, allowed to cool to ambient temperature then evaporated under reduced pressure. The residual solid obtained was washed with diethyl ether then filtered from solution, and sucked to dryness to give the required product as a pale brown solid, 3.97 g. 1H NMR (CDCl3) δ: ca 11.0 (1H, bs), 9.33 (1H, m), 8.66 (1H, d), 8.42 (1H, s), 7.74 (1H, m), 4.45 (2H, q), 1.44 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:18])=[CH:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-])=O.Cl[Sn]Cl>>[CH3:1][C:2]1[O:3][C:4]([CH3:18])=[CH:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[NH2:15]
Reactant: Cc1ccc(Sc2cc(C)oc2C)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Sc2cc(C)oc2C)c(N)c1

Procedure:
The product from Example 91a was reduced with SnCl2 following the procedure from Example 1f to give the title compound.
Reaction SMILES: Cl.[CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:24])[CH:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:14])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[C:25]([Cl:28])(=[O:27])[CH3:26]>C1C=CC=CC=1>[ClH:28].[C:25]([O:24][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([S:5][CH:2]([CH3:4])[CH3:3])=[CH:7][CH:8]=1)[CH:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:14])(=[O:27])[CH3:26]
Reactant: CCCCCCCCNC(C)C(O)c1ccc(SC(C)C)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCNC(C)C(OC(C)=O)c1ccc(SC(C)C)cc1

Procedure:
To 15 gr (40 mol) of 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol hydrochloride, 12,6 gr (160 mmol) of acetyl chloride are added. Heating is provided for 1 hour at reflux temperature, then 30 ml of benzene are added, reflux being maintained for two further hours. When cooling, the resulting solution abandons a white solid. The latter is filtered, then recrystallised from benzene. The product then weighs 11.5 gr (28 mmol, 70%) and melt at 167.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[NH2:40])[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[NH2:40][C:39]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=1[NH:29][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D,L-alanine (3.76 g, 19.9 mmol) and triethylamine (2.76 mL, 19.9 mmol) in THF (25 mL) was added 2-methylpropyl chlorocarbonate (2.58 mL, 19.9 mmol) under ice-cooling, and the mixture was stirred for 30 min. To this solution was added dropwise a solution of methyl 3,4-diaminobenzoate (3.00 g, 18.1 mmol) in THF (15 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained residue was triturated with ethyl acetate to give the title compound (4.21 g, yield 69%).