Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:21][Mg+].[Br-].O>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:3]=1[C:4](=[O:5])[CH3:21]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cc(-c2cccc(F)c2)ccc1F
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-N-methoxy-N-methyl-benzamide (1.8 g, 6.5 mmol, 1.0 eq) in THF (14 mL) at −20° C. was added MeMgBr (3.2 mL, 9.7 mmol, 1.5 eq). The mixture was stirred at 0° C. for 2 h then water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 20:1 to 10:1) to give the title compound as a white solid (1.3 g, 86%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@@H:13]([NH:33][C:34](=[O:40])OC(C)(C)C)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]3[C:28]([CH:29]([OH:31])[CH3:30])=[CH:27][CH:26]=[CH:25][N:24]3[CH:32]=2)=[CH:17][CH:16]=1.Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O>[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])[C:34]([NH:33][C@@H:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]3[C:28]([CH:29]([OH:31])[CH3:30])=[CH:27][CH:26]=[CH:25][N:24]3[CH:32]=2)=[CH:17][CH:16]=1)[CH2:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11])=[O:40]
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Reactant: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)NC(=O)OC(C)(C)C)cc3)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
A mixture of 1,1-dimethylethyl [(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4M HCl in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness, redissolved in DMF (30 mL), and to this solution was added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) and pentafluorophenyl 3-chloro-4 [(1-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na2SO4), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS(ES+) m/e 637 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[C:21]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:21]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:28]
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C1CCCC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CCCC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.1 g, 0.37 mmol; prepared in a manner similar to that described in Example 23), glutaric anhydride (0.042 g, 0.37 mmol) and toluene (10 ml) was heated under reflux until the starting materials were consumed (the reaction was followed by tic using a 3:1 mixture of ethyl acetate and ethanol as eluant), then it was allowed to cool to ambient temperature. The resulting solid was collected by filtration and recrystallised from ethanol to give 4-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]butyric acid (0.08 g) as a white solid, mpt. 190–194° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.5–1.65 (m, 2H) (—CH2CH2CH2—), 2.0–2.25 (m, 4H) (—CH2CH2CH2—) 4.1 (s, 2H) (ArCH2—), 6.8–7.0 (m, 2H) (2×ArH), 7.5–7.8 (m, 4H) (4×ArH), 8.05 (d, 1H) (ArH), 9.45 (s, 1H) (chain CONH), 12.85 (br s, 1H) (—CO2H), 12.4 (s, 1H) (ring CONH); m/z (M−H)+. 382, 100% purity.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[N+:12]([CH2:13][CH2:14][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:11][C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[CH:8]=3.[OH-].[Na+].[CH3:21][C:22]([CH3:24])=[O:23]>>[CH2:21]([CH:11]1[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[CH:8]=[C:7]2[N:12]1[CH2:13][CH2:14][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=12)[C:22]([CH3:24])=[O:23]
Reactant: CC(C)=O
Reactant: c1ccc2c(c1)CC[n+]1cc3ccccc3cc1-2
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC1c2ccccc2C=C2c3ccccc3CCN21

Procedure:
In the first step of the reaction scheme, 5,6-dihydrodibenzo[a,g]quinolizinium salt of formula (II) is reacted with acetone in the presence of a base such as sodium hydroxide to give 8-acetonyl-5,6-dihydrodibenzo[a,g]quinolizine compound of the formula (III).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH:3]=1.[CH2:19]([O:21][C:22](=[O:29])[CH2:23][C:24](=O)[CH:25]([CH3:27])[CH3:26])[CH3:20]>CCO>[CH2:19]([O:21][C:22]([C:23]1[C:24]([CH:25]([CH3:27])[CH3:26])=[N:8][C:5]2[C:4]([C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:29])[CH3:20]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: COc1ccccc1C#Cc1cc(Cl)ccc1N
Solvent: CCO
Product: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1OC
Yield: 32 %

Procedure:
The title compound was prepared in analogy to example 10 step B from 4-chloro-2-(2-methoxy-phenylethynyl)-phenylamine (200 mg, 0.78 mmol) and 4-methyl-3-oxo-pentanoic acid ethyl ester (0.2 ml, 1.16 mmol) in anhydrous EtOH (8 ml). Light green liquid. (100 mg, 32% yield). LC-MS (ESI): 398 (M+H)+.
Reaction SMILES: C([C@@:8]1([O:22][C@H:21]([CH2:23][O:24]CC2C=CC=CC=2)[C@@H:20]([F:32])[C@H:11]([O:12]CC2C=CC=CC=2)[C@H:10]1[NH:33][C:34](=[O:36])[CH3:35])[OH:9])C1C=CC=CC=1>CC(O)=O.[Pd].C>[C:34]([NH:33][C@@H:10]1[C@@H:11]([OH:12])[C@H:20]([F:32])[C@@H:21]([CH2:23][OH:24])[O:22][CH:8]1[OH:9])(=[O:36])[CH3:35]
Reactant: CC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](F)[C@@H](COCc2ccccc2)O[C@@]1(O)Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](F)[C@@H]1O
Reaction time: 120 h

Procedure:
A solution of benzyl2-acetamido-3,6-di-O-benzyl-2,4-dideoxy-4-fluoro-α-D-glucopyranose (3.21 g, 6.51 mmol) in the HOAc (150 ml) containing 10% Pd/charcoal catalyst (4.3 g) was hydrogenated at 50–55 psig. Pressure dropped from 55 to 50 psig and was re-pressurized to 56 psig. Again, pressure dropped to approximately 50 psig. A small sample was withdrawn. The reaction appeared to have made a little progress, but much starting material remained as shown by TLC. Catalyst was removed by filtration through a layer of Celite, which was washed with H2O and EtOH. The filtrate was evaporated in vacuo to low bulk then again clarified by filtration through a layer of Celite. This filtrate was now evaporated in vacuo to a dry solid, which was dried in vacuo for 18 hours. Yield=2.57 g. The reaction was then re-started by dissolving 2.01 g (5.09 mmol) of the product in glacial HOAc (50 ml) containing 2.65 g of 10% Pd/charcoal catalyst, using a Parr shaker apparatus, to hydrogenate at 50 psig for 5 days. A sample was withdrawn, membrane-filtered, then evaporated in vacuo to a residue. This material was checked via TLC and the reaction appeared to have been successful, although a small amount of unknown material showed just ahead of the product. The remainder of the reaction catalyst was removed by filtration through a layer of Celite. The filtrate was evaporated in vacuo to a residue, which was dried in vacuo 18 hours; Yield=2.67 g. This material was now triturated in warm absolute EtOH (approx. 25 ml). Ether was added, in portions (250–300 ml). A tan solid appeared. The supernatent liquid was removed by decontation; the residue was dried in vacuo Yield=1.35 g (54.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Br:24])[C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C/c1c(C)cccc1OCCCC(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: Clc1ccccc1
Product: CCOC(=O)/C=C/c1c(CBr)cccc1OCCCC(=O)OCC
Temperature: 85 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 4-[2-((E)-2-ethoxycarbonyl-vinyl)-3-methyl-phenoxy]-butyric acid ethyl ester (8.0 g, 25.0 mmol) in chlorobenzene (190 mL) were added N-bromosuccinimide (6.67 g, 37.5 mmol) and 2,2′-azobisisobutyronitrile (AIBN) (591 mg, 3.6 mmol) at room temperature. Then, the solution was heated to 85° C. and stirred for 1 h. Then, the reaction mixture was cooled to room temperature and diluted with water (100 mL). Then, the organic compound was extracted into hexanes (3×100 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a crude oil. The crude oil was purified by using a Biotage (40 L) column eluting with 15-25% ethyl acetate in hexanes to isolate 4-[3-bromomethyl-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (7.11 g, 71%) as a low melting solid: ES(+)-HRMS m/e calculated for C18H23BrO5 (M+Na)+ 421.0621, found 421.0621.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]#[N:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([CH3:14])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C#N)[nH]n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(C)(C)C)cc1CN

Procedure:
3-tert.-butyl-1H-pyrazol-5-carbonitrile (J-IV) (10 mmol) was added to a suspension of NaH (60%) (12.5 mmol) in DMF (20 ml) at room temperature while stirring. After stirring for 15 minutes, methyl iodide (37.5 mmol) was added dropwise to this reaction mixture at room temperature. After stirring for 30 min at 100° C., the reaction mixture was mixed with water (150 ml) and extracted with dichloromethane (3×75 ml). The combined organic extracts were washed with water (100 ml) and sat. NaCl solution (100 ml) and dried over magnesium sulphate. After removal of the solvent under vacuum, the residue was purified by column chromatography (SiO2, various mixtures of EE and cyclohexane as the mobile solvent) and the product J-V was obtained.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.S([O-])([O-])(=O)=S.[Na+].[Na+].[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.[K]>O.C1(C)C=CC=CC=1.C(#N)C>[C:46]1(=[O:56])[N:50]([CH2:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4]2)[C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC1CCc2ccccc2N1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [K]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1CCc2ccccc2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of 2-hydroxymethyltetrahydroquinoline (10 g, 61 mmol), imidazole (10.0 g, 147 mmol), and triphenylphosphine (19.0 g, 72.4 mmol) in a mixed solvent of 5:1 toluene/acetonitrile (360 mL) was added iodine (16.85 g, 66.4 mmol) at 0° C. The mixture was stirred for 2 h at 0° C. and aqueous sodium thiosulfate was added. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and insoluble materials were removed by filtration. The filtrate was concentrated and the residue was dissolved in DMF (60 mL) and potassium phthalimide (13.6 g, 73.48 mmol) was added. The mixture was heated at 60° C. for 2 h and diluted with water (200 mL). The mixture was extracted with 1:1 toluene/ethyl acetate (200 mL×2). The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified with silica gel column chromatography with 10:1 to 6:1 hexane/ethyl acetate to give 10.25 g of 2-Phthalimidomethyltetrahydroquinoline (75%): 1H NMR (270 MHz, CDCl3) δ7.86 (m, 2H), 7.74 (m, 2H), 6.95 (m, 2H), 6.59 (t, 1H, J=8 Hz), 6.49 (d, 1H, J=8 Hz), 3.91 (dd, 1H, J=14, 5 Hz), 3.78 (dd, 1H, J=14, 5 Hz), 3.68 (m, 1H), 2.78 (m, 2H), 2.00 (m, 1H), 1.69 (m, 1H).
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[Cl-:16].[Ca+2].[Cl-]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:16][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4]
Reactant: [Cl-]
Reactant: CCCCCCCCCCC(Br)C(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [Ca+2]
Solvent: CC#N
Product: CCCCCCCCCCC(Cl)C(=O)O

Procedure:
To 2-bromododecanoic acid (1 g), after having been dissolved in acetonitrile (50 ml ), were added calcium chloride (2 g) and tetraethylammonium chloride (1 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 2-chlorododecanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][O:22][CH2:23][CH2:24][O:25]C=C)=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:28])[CH:3]=1.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:28])[CH:3]=1
Reactant: C=COCCONC(=O)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide (445 mg, 0.95 mmol) in CH2Cl2 (10 mL) was added 1.0 N HCl solution (6.7 mL, 6.72 mmol). After stirring for 1 h, the reaction mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic layer was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) and gave the desired product (white solid, 347 mg, 65% yield for two steps). 1H NMR (400 MHz, MeOD): δ 8.65 (s, 1H), 7.8 (s, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.24 (m, 1H), 6.50 (m, 1H), 3.95 (s, 2H), 3.70 (s, 2H). MS APCI (+) m/z: 445.9[M+H], 467.8, [M+Na].
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:16]=1[NH2:17])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)(=O)C.ClCCl>[CH3:24][CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:15]([CH:12]([CH3:14])[CH3:13])[C:16]=1[NH:17][C:3](=[O:4])[CH:2]([Br:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:23]
Reactant: O=C(Cl)C(Br)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
The α-bromophenylacetylchloride (21.0 g, 89.7 mmol) was added slowly via pipet to a cooled (0° C.) solution of 2,6-diisopropylaniline (15.9 g, 89.7 mmol) and triethylamine (12.5 mL, 89.7 mmol) in ethyl acetate (1600 mL). The resulting slurry was warmed (25° C.) then stirred (1 hour). The resulting mixture was diluted with ethyl acetate (1000 mL) and dichloro methane (500 mL), then washed with water (1000 mL), with 0.5N aqueous HCl (2×1000 mL), with saturated aqueous sodium bicarbonate (1×600 mL), with brine (1×600 mL), then dried (MgSO4) and concentrated to a solid. The solid was recrystallized from ethyl acetate to yield 27.2 g (81.0%) of (±)-N-[2,6-bis(1-Methylethyl)phenyl]-α-bromobenzeneacetamide as a white solid, mp 207°-209.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[C:16]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[C:16]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(-c3ccsc3)n2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccsc3)n2)CC1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-chloro-6-thiophen-3-yl-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (169 mg, 0.29 mmol) in 2-propanol/EtOAc (10:1, 11 mL) at room temperature was added DIEA (0.5 mL). The resulting solution was vacuum-flushed with N2 and then treated with 10% Pd/C (50 mg). The resulting suspension was exposed to H2 via balloon and heated to 65° C. After 3 h, 10% Pd/C (50 mg) was added, and the reaction mixture was heated at 65° C. overnight under H2. The resulting mixture was filtered to remove catalyst; the filtrate was concentrated and the residue was purified by preparative TLC (EtOAc/hexanes, 1:2) to yield a white solid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[CH:5][C:4]=1C1C=CC(C)=CC=1)[CH3:2].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>C(O)C.[OH-].[Na+]>[OH:33][C@@H:30]([CH2:31][OH:32])[CH2:29][O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:10])[CH:5]=2)=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccc(C)cc1
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccccc1C
Temperature: 60 °C
Reaction time: 14 h

Procedure:
A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (18 mg, 48 μmol) in ethanol (1.5 mL) and 3 N aq. NaOH (0.3 mL) is treated with (S)-3-chloro-propane-1,2-diol (30 μL) and the mixture is stirred at 60° C. for 14 h. The solvent is removed in vacuo and the residue is separated on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-o-tolyl-thiophen-2-yl)-propan-1-one (4 mg) as a colourless resin; LC-MS: tR=1.04 min, [M+1]+=453.28; 1H NMR (CDCl3): δ 7.45 (s, 1H), 7.92-7.08 (m, 4H), 6.87 (s, 2H), 4.11-4.04 (m, 1H), 3.87-3.80 (m, 4H), 3.16-3.10 (m, 2H), 2.97-2.90 (m, 2H), 2.64 (q, J=7.6 Hz, 2H), 2.24 (s, 3H), 2.17 (s, 6H), 1.20 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.[CH2:38]([CH2:40][NH2:41])[OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([NH:41][CH2:40][CH2:38][OH:39])=[O:37])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(O)/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Product: O=C(/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1)NCCO
Yield: 60 %

Procedure:
The title compound was prepared as described in Example 34. B using (2E)-3-(4-{[2-(4-fluorophenyl)-6-(phenylmethoxy)(1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)prop-2-enoic acid (0.494 g, 1.0 mmol) and ethanolamine (0.122 g, 2.0 mmol) to provide the title compound (0.322 g, 60% yield): 1H NMR (CDCl3) 8.02 (br, 1H), 7.61 (d, 1H), 7.32-7.41 (m, 7H), 7.00 (d, 2H), 6.91 (m, 2H), 6.69-6.77 (m, 5H), 6.37 (d, 1H), 6.12 (t, 1H), 5.03 (s, 2H), 4.75 (t, 1H), 3.80 (t, 2H), 3.57 (t, 2H), 3.45-3.56 (m 2H), 3.15 (dd, 1H), 2.89 (m, 2H), 2.66 (dt, 1H); ES-MS m/z 537 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:27]=[C:28]([C:2]2[S:6][C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH3:23])=[CH:4][CH:3]=2)[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(Br)s1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 310D using 1-[(5-bromo-2-thienyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 314B) and [3,5-bis(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 531 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.FC(F)(F)S(O)(=O)=O.[F:21][C:22]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27]([F:34])[C:23]=1[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[C:12]([C:24](=[O:25])[C:23]3[C:27]([F:34])=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=3[F:21])[C:3]=12
Reactant: N#Cc1cnc2[nH]ccc2c1Cl
Reactant: O=C(Cl)c1c(F)ccc([N+](=O)[O-])c1F
Agent: O=S(=O)(O)C(F)(F)F
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc([N+](=O)[O-])c3F)c2c1Cl
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 13.1 %

Procedure:
In a vial, 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (50, 500 mg, 2.82 mmol) is cooled in an ice water bath, and trifluoromethanesulfonic acid (2.49 mL, 28.15 mmol) is added. The solution is stirred at 0-5° C. for 5 minutes, then 2,6-difluoro-3-nitro-benzoyl chloride (49, 748.5 mg, 3.38 mmol) is added. The reaction is stirred at 0-5° C. for 1 hour, then warmed to room temperature and stirred for 4 days. The reaction is quenched with 5 mL of methanol, and stirred at room temperature for 1 hour. The reaction is poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer is washed with water, brine, dried with magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 0-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (51, 134 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]([N+]([O-])=O)=[CH:9][NH2:10].[CH3:14][S:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19]>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:16]([S:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NC=C(SCc1ccco1)[N+](=O)[O-]
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccco1
Yield: 50.4 %

Procedure:
A solution of 2-[(2-furanylmethyl)thio]-2-nitroethenamine (3.14 g.) and 1,1-bis-(methylthio)-2-nitroethene (13.2 g.) in dioxan (100 ml.) was heated at 100° for 11/2 hours. The solution was evaporated in vacuo and the residue suspended in warm ethyl acetate (70 ml.). The cooled suspension was filtered and the filtrate evaporated in vacuo. The oily residue was suspended in ether and the solid which separated was filtered and crystallised from ethanol to give the title compound (2.17 g.), m.p. 68°-70°. TLC (silica/ether-cyclohexane, 4:1) RF 0.3