Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[Al+3:6].[Cl-].[Cl-].[C:9]1([CH3:15])[CH:14]=CC=C[CH:10]=1>>[N-:1]=[N+:2]=[N-:3].[CH2:10]([Al+:6][CH2:14][CH:9]([CH3:10])[CH3:15])[CH:9]([CH3:15])[CH3:14]
Reactant: [Al+3]
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)C[Al+]CC(C)C
Temperature: 25 °C

Procedure:
1.235 g of granular sodium azide (19 mmol) are added to a cold solution of dilsobutyl aluminium chloride (19 mmol, 1.8M in toluene) diluted in 5 ml of toluene and the mixture is stirred at room temperature over the night to give diisobutyl aluminium azide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:9]([CH:11]1[CH2:13][CH2:12]1)=O)[C:6](=O)[CH3:7])[CH3:2].[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:7])=[N:25][N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:27])[F:26])[CH:19]=2)[C:9]=1[CH:11]1[CH2:13][CH2:12]1)=[O:14])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(=O)C1CC1
Reactant: NNc1cccc(OC(F)(F)F)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Yield: 79 %

Procedure:
To a solution of intermediate 11A, 2-cyclopropanecarbonyl-3-oxo-butyric acid ethyl ester (2.0 g, 10 mmol) in acetic acid (10 ml), cooled at 5° C., was added a solution of (3-Trifluoromethoxy-phenyl)-hydrazine (2.1 g, 11 mmol) in acetic acid (10 ml). The reaction was allowed to come to room temperature (1 h) after which time the reaction was concentrated, the residue dissolved in DCM, washed with saturated NaHCO3, (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 1:9) afforded 5-cyclopropyl-3-methyl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.8 g, 77%). Saponification of the ester with NaOH in analogy to intermediate 6 affords the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:32]([O:39][CH2:40][CH:41]=[O:42])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([CH:41]([OH:42])[CH2:40][O:39][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(O)CO[Si](C)(C)C(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester (Description 1; 10 g, 34.4 mmol) in tetrahydrofuran (100 ml) was cooled to −78° C. Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 50 ml, 50 mmol) was added dropwise and the mixture stirred, allowing to warm to room temperature over 1.5 hours. The orange solution was re-cooled to −78° C. and (tert-butyldimethylsilyloxy)acetaldehyde (10 g, 57.3 mmol) added. The mixture was allowed to warm to room temperature over 2.5 hours, then quenched with saturated aqueous ammonium chloride solution. The reaction mixture was partitioned between diethyl ether and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5-15% diethyl ether/dichloromethane, to give the title compound (12.4 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:17])=[CH:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:10]2[N:17]=[C:24]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]=2[CH:14]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc(N)c(Nc2ccc(F)cc2)c1
Product: COc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1

Procedure:
N2-(4-Fluorophenyl)-4-methoxybenzene-1,2-diamine was reacted analogously to Example 11d with pyridine-3-carbaldehyde.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)=[O:26].[OH-].[Na+]>>[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:30][CH:29]=1)=[O:26]
Reactant: O=C(Nc1ccc(O)cc1)c1cccc(F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NC(=O)c3cccc(F)c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 3-Fluoro-N-(4-hydroxy-phenyl)-benzamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26FNO6 [M+H]+: 468.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])O.[Na+].[Br:22][C:23]([CH3:28])([CH3:27])[C:24](Br)=[O:25]>C(Cl)(Cl)Cl.O1CCCC1>[Br:22][C:23]([CH3:28])([CH3:27])[C:24]([NH:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]([C:12]([F:13])([F:14])[F:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:25]
Reactant: COC(=O)c1cc(N)c(O)cc1C(F)(F)F
Reactant: CC(C)(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(NC(=O)C(C)(C)Br)c(O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
Methyl 5-amino-4-hydroxy-2-(trifluoromethyl)benzoate (53.0 g) was dissolved in chloroform (200 ml) and tetrahydrofuran (200 ml), and thereto was added an aqueous sodium hydrogen carbonate solution (27.60 g/240 ml), and the mixture was vigorously stirred. The mixture was cooled in an ice-bath, and thereto was slowly added dropwise 2-bromoisobutyryl bromide (65.5 g), and the mixture was stirred for 30 minutes. The mixture was warmed to room temperature, and further stirred for 2.5 hours. After the reaction was complete, the mixture was extracted twice with chloroform (300 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 5-[(2-bromo-2-methylpropanoyl)amino]-4-hydroxy-2-(trifluoromethyl)benzoate. This crude product was diluted in N,N-dimethylformamide (500 ml), and thereto was added potassium carbonate (60.53 g), and the mixture was stirred at 50° C. for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, and the obtained solid was removed by filtration. To the filtrate was added ethyl acetate (500 ml), and the mixture was washed with a 1N hydrochloric acid (500 ml) and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was crystallized from ethyl acetate/hexane (5/1, 200 ml) to give the title compound (48.5 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6][C:5]1=[O:19])([CH3:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]([N:4]1[CH2:8][C:7]2([CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:12]=3[O:13][CH2:14]2)[O:6][C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)N1CC2(COc3ccccc3OC2)OC1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1CC2(COc3ccc([N+](=O)[O-])cc3OC2)OC1=O
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
A solution of 3'-isopropyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one (24.8 g.; 94.2 mmole) in acetic acid (100 ml.) is cooled in an ice bath to the point at which freezing begins. A mixture of 90% nitric acid and concentrated sulfuric acid (54 mls., containing 1.2 ml. of nitric acid (d 1.5) to each 10 ml. of sulfuric acid, (ca. 124 mmole) is added dropwise with stirring over a period of 20 minutes, the cooling bath then is removed and stirring continued for 2 hours. A slight rise in the temperature of the reaction mixture will be noticed (to 34° C.) and the color darkens slightly. The nitration can be followed by thin layer chromatography (TLC) on silica gel using multiple development with 1:1 carbon tetrachloride/chloroform. The reaction mixture is poured into water (400 ml.) and the crude product extracted with methylene chloride (3 × 100 ml.). After washing the extract successively with water (100 ml.), 10% sodium carbonate (75 ml.) and again with water (100 ml.), it is dried over magnesium sulphate and evaporated to a syrup. The syrup is crystallized by boiling it with ethanol (50 ml.) yielding 15.58 g. (53.8%) of 3'-isopropyl-7-nitro-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one, m.p. 140°-144° C. and a second crop is obtained by concentrating the mother liquor to ca. 25 ml. to give an additional 3.44 g. (11.8%) of compound, m.p. 130°-140° C.
Reaction SMILES: [C:1](#[N:3])C.[CH3:4][C:5]([O-])([CH2:7][CH3:8])[CH3:6].[K+].C(OCC)(=O)C(C)C.Cl.[C:20]1([CH3:28])[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.Cl>C1COCC1.C(O)C>[CH:5]([C:7]1[CH:8]=[C:1]([NH2:3])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:28])=[CH:21][CH:22]=2)[N:27]=1)([CH3:6])[CH3:4]
Reactant: CCC(C)(C)[O-]
Reactant: Cc1ccc(NN)cc1
Reactant: CC#N
Agent: CCOC(=O)C(C)C
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)C)cc2N)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a mixture of acetonitrile (0.50 mL, 9.57 mmol) in THF (30 ml) at RT was added potassium 2-methylbutan-2-olate (1.7M solution in 2-methyl-butan-2-ol, 16.9 mL, 28.7 mmol). On completion of the addition ethyl isobutyrate (5.12 mL, 38.3 mmol) was added dropwise and the mixture was maintained at RT for 16 hr. The reaction mixture was concentrated in vacuo to ca 20 mL, was diluted with ethanol (20 mL) and p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) was added. The resulting mixture was acidified to pH1 by the addition of conc. hydrochloric acid and the mixture was then heated to 70° C. for 2 hr. The mixture was cooled to RT and was concentrated in vacuo to ca 20 mL and then diluted with water (30 mL). The aq. mixture was adjusted to pH12 by the addition of aq NaOH solution (6M) and was then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (30 mL) and then dried (MgSO4) and evaporated in vacuo to afford the title compound as a brown oil (1.78 g, 90% pure, 72%); Rt 1.32 min (Method 2); m/z 216 (M+H)+ (ES+). This material was used directly in the next step, without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)=[O:7].C[N:22](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:22])=[O:20])=[CH:14]2)=[O:7]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a mixture of 7-[(2-thienylcarbonyl)amino]-1H-indole-2-carboxylic acid (100 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (63 mg) and N,N-dimethylformamide (5 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (80 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (97 mg, yield 98%) as pale-brown crystals. melting point 289-290° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+:4].[C:5]([OH:8])(=[O:7])[CH3:6]>C(O)C>[CH3:3][CH2:2][O:1][CH2:5][CH3:6].[C:5](=[O:7])([OH:1])[O-:8].[Na+:4]
Reactant: CC[O-]
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CCO
Product: CCOCC
Product: O=C([O-])O
Reaction time: 0.33 h

Procedure:
The 300 mg of oil was dissolved in 1.5 ml of ethanol and treated with 140 μl of 2.2N sodium ethoxide under argon. After 20 minutes, 80 μl of acetic acid was added and the volatiles removed. Ether/sodium bicarbonate workup gave 260 mg of the desired compound
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.CO>ClCCl>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[O:29])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(=O)N1CCN(N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CCN(NC(=O)Nc2ccc(F)cc2)CC1
Yield: 71.4 %

Procedure:
To a solution of 1-acetyl-4-aminopiperazine dihydrochloride (540 mg) in dichloromethane (5 ml) was added dropwise triethylamine (0.8 ml) followed by addition a solution of 4-fluorophenylisocyanate (377 mg) in dichloromethane (2.5 ml) with stirring in an ice bath. After stirring for 100 minutes at the same temperature, a mixture of dichloromethane (15 ml) and methanol (3 ml) was added to the reaction mixture. The mixture was washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethanol to yield N-(4-acetyl-1-piperazinyl)-N'-(4-fluoroph-enyl)urea (500 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:17][CH2:18][CH:19]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:17][CH2:18][CH2:19][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6]=1[CH3:7]
Reactant: C1COCCN1
Reactant: Cc1c(I)cnn1CC1(OCCC=O)CCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(I)cnn1CC1(OCCCN2CCOCC2)CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 155C (393 mg) in dichloromethane (20 mL) was added morpholine (263 mg) and sodium triacetoxyborohydride (427 mg). After the reaction mixture was stirred overnight at room temperature, 2N NaOH aqueous solution (10 mL) was added and the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated NaCl solution. After the organic layer was dried over Na2SO4, it was filtered and the solvent was evaporated under reduced pressure. The crude product was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]=3)[C:10]([CH3:31])=[CH:9]2)=[CH:5][CH:4]=1>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]=3)[C:10]([CH3:31])=[CH:9]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2cc(C)c3ccc(C(=Cc4ccncc4)c4ccccc4)cc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C)c3ccc(C(Cc4ccncc4)c4ccccc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
A solution of cis- and trans-[1-(4-methoxybenzyl)-3-methyl-6-(1-phenyl-2-pyridin-4-yl-vinyl)-1H-indole (70 mg, Example 22) in a mixture of tetrahydrofuran and methanol (20 ml; 1:1, v/v) was heated at 45-50° C. under an atmosphere of hydrogen in the presence of 6% palladium on activated charcoal then stirred overnight at room temperature. The mixture was filtered through celite then evaporated. The residue was subjected to high pressure liquid chromatography using a hypersilC18 BDS column (250×20 ml, 8 micron) and eluting with methanol containing 0.1% ammonium hydroxide to yield the title compound (13 mg) as an oil. NMR (CDCl3): δ 2.30(s,3H); 3.30-3.40(m,2H); 3.70(s,3H); 4.30-4.40(m,1H); 5.10(s,2H); 6.80-7.50(m,13H); 8.30-8.35(m,2H); 8.50(bs,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:21]([F:24])([F:23])[F:22])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:21]([F:24])([F:23])[F:22])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CSc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
After adding 1.44 g of toluene to 0.48 g (1.17 mmol) of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl) butan-1-one, 0.28 g (2.34 mmol) of thionyl chloride and 0.19 g (2.34 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction was traced by high-performance liquid chromatography. Since the raw materials did not disappear, 0.14 g (1.17 mmol) of thionyl chloride and 0.09 g (1.17 mmol) of pyridine were added and stirred for 1 hour. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.14 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.37 g of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)-2-buten-1-one (yield 81.8%).
Reaction SMILES: [Br:1][CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6]C.CC1C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.[C:26]([O-:29])(O)=O.[Na+]>CC(OC)(C)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:26][O:29][CH:25]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CCCCCC(O)Br
Reactant: O=C([O-])O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: COC(C)(C)C
Product: BrCCCCCCOC1CCCCO1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Bromohexanol (54.67 g) is dissolved in TBME (250 mL) and dried over Na2SO4. After filtration, TsOH (0.6 mmol) is added and the solution is cooled in an ice bath. 3,4-Dihydropyran (394 mmol) is added dropwise, while maintaining the temperature around 2-3° C. After complete addition the reaction mixture is allowed to reach ambient temperature overnight. The mixture is ished with sat. NaHCO3 (2×200 mL). The aqueous layer is extracted with TBME (200 mL) and the combined organic layers are ished with brine (200 mL). After drying over Na2SO4 (containing some K2CO3), the solvent is evaporated to yield (XX) as a colourless oil (90%), which is stored at 4° C. over K2CO3 and is used without further purification.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.C1COCC1.[CH3:22][NH2:23]>O>[IH:1].[CH3:22][NH:23][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: CN
Reactant: CS(=O)(=O)Nc1ccc(SCCCI)cc1
Solvent: O
Solvent: C1CCOC1
Product: CNCCCSc1ccc(NS(C)(=O)=O)cc1
Product: I
Yield: 94 %

Procedure:
A solution of N-[4-(3-iodo-1-propylthio)phenyl]methanesulfonamide (4.8 g, 0.13 mol), THF (28 mL), and 40 wt % methylamine in water (56 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, taken up in 2:1 EtOH/toluene, and concentrated to give 4.9 g (94%) of product as a brown solid m.p. 80°-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[OH:22])[CH:3]=1
Reactant: O=Cc1ccco1
Reactant: Brc1ccc(CCI)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(Br)cc1C(O)c1ccco1
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
4-Bromo-2-iodoethyl benzene (50.0 g, 0.161 mol) is dissolved in anhydrous tetrahydrofuran (250 ml) and cooled to −70° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride (2 M solution in THF, 100 ml, 0.200 mmol) is added dropwise with vigorous stirring over 40 minutes, maintaining the internal temp below −60° C. by external cooling. When the addition is complete, the reaction is stirred at −70° C. for 20 minutes then allowed to warm to room temperature over 1 hour and 20 minutes. The reaction mixture is then cooled to −70° C. and a solution of 2-furaldehyde (16 ml, 18.6 g, 190 mmol) in tetrahydrofuran (50 ml) is added dropwise over 40 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (˜500 ml) is added and the mixture is extracted into ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel to give (5-bromo-2-ethylphenyl)-furan-2-ylmethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][N:5]([S:22](=[O:32])(=[O:31])[NH:23]C(OC(C)(C)C)=O)[C:6]1[C:11]([F:12])=[CH:10][C:9]([Br:13])=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[CH2:4][N:5]([S:22](=[O:31])(=[O:32])[NH2:23])[C:6]1[C:11]([F:12])=[CH:10][C:9]([Br:13])=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CN(c1c(F)cc(Br)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN(c1c(F)cc(Br)cc1OCc1ccccc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.25 g (2.28 mmol) of N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-4-bromo-6-fluorophenyl)glycine methyl ester in 6 mL of methylene chloride is added 6 mL of TFA. The solution is stirred at room temperature for 20 min. then the solvent is removed under reduced pressure. The residual oil is purified by flash chromatography using 15% ethyl acetate in methylene chloride to elute the product as an oil: 1H NMR (CDCl3) δ 7.48-7.36 (m, 5H), 7.02-6.98 (m, 2H), 5.10 (d, J=4.30 Hz, 2H), 4.94 (s, 2H), 4.34 (q, 2H), 3.70 (s, 3H); MS (M−H)−=447.
Reaction SMILES: [Br:1][C:2]1([Br:12])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Br:13]Br.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.O>[Br:12][C:2]1([Br:1])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1Nc2ncc(Br)cc2C1(Br)Br

Procedure:
A solution of 3,3-dibromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (5.0 g, 13.4 mmol) in tert-BuOH (100 mL) and water (100 mL) was stirred at room temperature and bromine (5.5 g, 34.3 mmol) was added dropwise over min. A saturated aqueous solution of sodium bicarbonate (approx. 15 mL) was added dropwise over 30 min to raise the pH of the solution to 6.5. The yellow solid formed was collected by filtration. The filtrate was condensed to approx. 100 mL and extracted with CHCl3 (2×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to leave a yellow solid. The solids were combined and dried under vacuum to give 3,3,5-tribromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one as a yellow solid, 6.25 g (98%). 1H NMR (CDCl3) δ 9.4 (br s, 1H), 8.28 (d, 1H, J=2 Hz), 7.95 (d, 1H, J=2 Hz).