Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[C:7]([Cl:20])[C:6]=1[CH3:21])(=[O:3])[CH3:2].[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:15][CH:14]=2)=[C:7]([Cl:20])[C:6]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1C
Reactant: CC(C)C(=O)Cl
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)cc2)c(Cl)c1C
Yield: 88.3 %

Procedure:
Methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl] acetate (33 mg, 0.10 mmol), was coupled with isobutyryl chloride (11 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether), 35 mg (95%) of methyl-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenyl] acetate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 30 mg (89%) of 3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][C:7]([C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1)=[O:8].[OH-].[Na+]>O>[Cl:5][CH2:4][CH2:3][CH2:2][O:15][C:14]1[CH:16]=[CH:17][C:9]([C:7](=[O:8])[CH3:6])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCl
Temperature: 86 °C

Procedure:
To a mixture of 15.15 kg (96.26 mole) of 1-bromo-3-chloropropane and 25 liter of water heated to 86° C. was added a solution of 8 kg (48.13 mole) of acetovanillone in 3.93 kg (48.6 mole) of 50% aqueous sodium hydroxide and 89 liter of water over a 2.5 hr period. The mixture was heated at 80°-85° C. for 2.5 hr after addition was complete. The mixture was cooled and extracted twice with 49 kg portions of toluene. The combined extracts were washed once with 1.9 kg of 50% sodium hydroxide diluted to 5 gal and once with 5 gal of water. The toluene layer was dried over 3 lb of anhydrous sodium sulfate and concentrated under reduced pressure. The residue was heated to reflux in 15 gal of isopropylether, filtered, and the filtrate cooled. The crystallized title compound obtained by filtration together with additional compound obtained by concentrating the filtrate to 25% of its original volume amounted to 4.2 kg (36%). Acetovanillone recovered was 3.4 kg. The product was recrystallized twice from cyclohexane and twice from ligroin, m.p. 57.8°-58.5° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:19]([CH:20]=[O:21])=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=[C:16]2[C:8]=1[C:9](=[O:25])[CH2:10][C:11]1([O:15]2)[CH2:14][CH2:13][CH2:12]1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:7]2[C:19]([CH:20]=[O:21])=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=[C:16]3[C:8]=2[C:9](=[O:25])[CH2:10][C:11]2([O:15]3)[CH2:14][CH2:13][CH2:12]2)=[CH:31][CH:30]=1
Reactant: CC(C)c1cc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)C(=O)CC1(CCC1)O2
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Reaction time: 8 h

Procedure:
Under argon, 4.00 g (9.84 mmol) of 6-formyl-7-isopropyl-4-oxo-3,4-dihydrospiro[chromen-2,1′-cyclobutan]-5-yl trifluoromethanesulfonate (Example 50A), 1.79 g (12.8 mmol) of 4-fluorophenyl-boronic acid, 3.55 g (16.73 mmol) of tripotassium phosphate and 1.25 g (1.08 mmol) of tetrakis(triphenylphosphine)palladium(0) are initially charged and the apparatus is flushed by repeated evacuation and venting with argon. 100 ml of abs. dioxane are then added, the apparatus is closed and the mixture is heated under reflux. After stirring overnight, the mixture is cooled and filtered through a layer of silica gel, the filter cake is washed thoroughly with ethyl acetate and the filtrate is concentrated. The residue is adsorbed on silica gel and chromatographed on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 25:1). The crude product obtained is triturated with hot petroleum ether and cooled slowly, and the precipitate is filtered off with suction. This gives 3.2 g of the target compound in a purity of about 90%.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: C1CSCCN1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCSCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 60 mg; 0.20 mmol) and thiomorpholine (0.20 mL; 2.0 mmol) to 250° C. under microwave irradiation according to the procedure described in Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-thiomorpholin-4-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (15 mg, 21%) as light brown powder. ES-HRMS m/e calcd for C19H29N4OS4 (M+H+) 361.2057, found 361.2053.
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].Cl.Cl.[N:8]1([C:14]2[CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[O:4]1[CH2:1][CH2:18][CH:19]([N:11]2[CH2:12][CH2:13][N:8]([C:14]3[CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:10]2)[CH2:14][CH2:15]1
Reactant: OCc1cccc(N2CCNCC2)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OCc1cccc(N2CCN(C3CCOCC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added to [3-(piperazin-1-yl)phenyl]methanol dihydrochloride (240 mg) to carry out liquid separation. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was mixed with dichloromethane (5 ml), and tetrahydro-4H-pyran-4-one (100 mg) and acetic acid (168 mg) were added thereto, followed by stirring at room temperature for 15 minutes. Sodium triacetoxyborohydride (576 mg) was added to the reaction mixture at 0° C., followed by stirring at room temperature for 5 hours. Water and CHCl3 were added to the reaction mixture, and the aqueous layer was adjusted to a pH of 8 to 9 by the addition of a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with water, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {3-[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}methanol (45 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:15][Si](C(C)(C)C)(C)C)[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:15])[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)CC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCC(O)CC(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-bromophenyl)-1-(tert-butyldimethylsilyloxy)hex-5-en-3-ol (18.8 g, 44.0 mmol) in tetrahydrofuran (60 mL) is added 1 M tetrabutylammonium fluoride solution in THF (66.0 mL, 66.0 mmol). The resulting mixture is stirred at room temperature for 2 hours. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product is purified by silica gel chromatography eluting with a linear gradient of 20% to 40% ethyl acetate in hexanes over 26 minutes to give the title compound as racemic diastereomeric mixture (11.8 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.38-7.36 (m, 1H), 7.28-7.24 (m, 1H), 7.22-7.17 (m, 1H), 5.83-5.75 (m, 1H), 5.15-5.11 (m, 2H), 5.03-4.89 (m, 1H), 4.00-3.90 (m, 1H), 2.32-2.21 (m, 2H), 1.96-1.89 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]C(C)(C)C.[NH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].Cl.O>C1COCC1>[NH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:16]
Reactant: Brc1ccccn1
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: NCC(O)(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.), stirred solution of 2-bromopyridine (0.38 mL, 4.0 mmol) in THF (40 mL) under Ar was added dropwise t-BuLi (5.2 mL, 8.8 mmol). After 30 min, 2-aminoacetophenone•HCl (687 mg, 4.00 mmol) was added as a solid in one portion. The reaction was allowed to slowly warm to RT as the bath warmed. Water was added and the reaction mixture was extracted with EtOAc, dried (MgSO4), filtered and concentrated to afford a solid. Purification by flash chromatography afforded 68 mg as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 8.50 (d, J=4.80 Hz, 1H), 7.70-7.19 (m, 8H), 3.72 (d, J=13.14 Hz, 1H), 3.38 (d, J=13.14 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:18][C:8]2=1)=O.[NH2:28][C:29]([NH2:31])=[S:30]>>[NH2:31][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:14])[C:9]2[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:18][C:8]3=2)[N:28]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Reactant: NC(N)=S
Product: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4csc(N)n4)ccc3n(C)c21

Procedure:
The process is carried out as for Example 21 above, using compound from Example 114A 6-(2-bromoacetyl)-3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and thiourea.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: NCCN1CCOCC1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCCN4CCOCC4)nc32)c(=O)[nH]c1=O

Procedure:
The subtitle product was prepared from the product of example 44 step (viii) (0.225 g) and 4-(2-aminoethyl)morpholine (0.38 ml) according to the method of example 51 step (i). Purification was by precipitation using diethyl ether with filtration to give the subtitle product as yellow solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[H][H]>[Pd].C(O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: [H][H]
Reactant: C1=CC2CC1CC2Cn1ccnc1
Agent: [Pd]
Solvent: CCO
Product: c1cn(CC2CC3CCC2C3)cn1

Procedure:
A mixture of 1-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)imidazole (2.0 g, 11.48 mmol) and palladium on charcoal (0.2 g, 10%) in dry ethanol was shaken in an atmosphere of hydrogen for 4.5 h. The reaction mixture was then filtered through Hyflo-Supercel, and the filtrate was concentrated under reduced pressure to afford a colourless oil. Distillation of the oil afforded 1-(bicyclo[2.2.1]heptan-2-ylmethyl)imidazole as a colourless oil, b.p. 82°-84°/0.15 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[F:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1cccc(C)c1CCl
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(F)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 4-fluoro-3-hydroxybenzoate (2.814 g, 15.3 mmol), K2CO3 (1.95 g, 14.1 mmol) in DMF (15 ml) was added 2,6-Dimethylbenzyl chloride (2.21 g, 14.3 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours at the room temperature, diluted with ethyl acetate and washed with water (2×), and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 4:1) to give the title compound.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:58]=1[OH:64])[CH3:56]>C(Cl)(Cl)Cl>[Br:1][C:61]1[CH:60]=[C:59]([F:63])[C:58]([OH:64])=[C:57]([CH2:55][CH3:56])[CH:62]=1
Reactant: CCc1cccc(F)c1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(F)c1O
Reaction time: 24 h
Yield: 57.8 %

Procedure:
A solution of tetrabutyl ammonium tribromide (4.2 g, 8.6 mmol) in CHCl3 (25 mL) was added to a stirred solution of 2-ethyl-6-fluoro-phenol (1.1 g, 7.9 mmol) dissolved in CHCl3 (25 mL). The reaction mixture was stirred for 24 hrs and then quenched with 5% solution of sodium thiosulfate (30 mL). The biphasic mixture was stirred for 30 mins and then the layers were separated. The organic layer was washed with 1N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (0–10% EtOAc in hexanes) to give the desired product (1 g, 60%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3 H), 2.65 (q, J=7.6 Hz, 2 H), 5.09 (d, J=4.8 Hz, 1 H), 7.06 (s, 1 H), 7.09 (d, J=11.9 Hz, 1 H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([NH:38][NH2:39])=[CH:30][CH:29]=1>>[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([N:38]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:24])([F:25])[F:26])(=[O:21])=[O:22])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:39]2)=[CH:30][CH:29]=1
Reactant: NNc1ccnc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and quinolin-4-yl-hydrazine according to the method described for example 43. MS: M=498.1 (M+H)+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]1=[O:16].[Br:17]Br.O>C(O)(=O)C>[Br:17][C:14]1[S:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:7](=[O:16])[C:8]=2[CH:15]=1
Reactant: BrBr
Reactant: O=C1c2ccsc2CCCN1CCCCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(Br)sc2CCCN1CCCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a solution of 3.0 g of 5-(4-chlorobutyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one in 20 ml of acetic acid was added dropwise a solution of 2.1 g of bromine in 5 ml of acetic acid for 10 minutes. After the mixture was stirred at room temperature for 3 hours, the mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to give 4.0 g of 2-bromo-5-(4-chlorobutyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one as a pale brown oil. The obtained compound was employed in the subsequent reaction without purification.
Reaction SMILES: C[C:2]1(C)[CH2:24][C:23](=O)[C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH2:3]1.[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)([OH:34])[CH2:30][CH2:29]1>>[OH:34][C:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:30][CH2:29][CH:28]([NH:27][C:20]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([O:10][CH2:9][C@H:6]2[C:5]4[CH:23]=[CH:24][CH:2]=[CH:3][C:4]=4[O:8][CH2:7]2)[CH:19]=[CH:18][CH:17]=3)=[O:21])[CH2:33][CH2:32]1
Reactant: CC1(C)CC(=O)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2C1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OC[C@@H]5COc6ccccc65)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-[(S)-1-(2,3-dihydro-benzofuran-3-yl)methoxy]-1H-indole-2-carboxylic acid 16h and amine 14.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]2[N:7]([C@@H:10]3[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[CH:8]=[N:9][C:5]=2[CH:4]=1.[Br:28]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:28][C:8]1[N:7]([C@@H:10]2[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:24]=[CH:25][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][C:5]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2cc(C(F)(F)F)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 115.7 %

Procedure:
To a refluxing solution of 0.2 g (0.52 mmol) of 5-Trifluoromethyl-1-(2,3-di-O-Acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole in 10 mL of dry THF was added 0.2 g (1.1 mmol) of N-bromosuccinimide (NBS). The reaction mixture was further refluxed for 10 min. Additional 0.1 g of NBS was added. After 5 min, the mixture was poured into an ice-cooled solution of 20 mL CHCl3 and 20 mL sat. NaHCO3. The CHCl3 solution was separated and was further washed with sat. NaHCO3. After drying (MgSO4) and solvent removal, 0.28 g of the title compound was obtained as a semi-solid which was used without further purification in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:34]=[C:35]([NH2:45])[C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([OH:43])=[C:38]([CH3:44])[CH:37]=1>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[C:9]2[O:11][N:45]=[C:35]([C:36]3[CH:41]=[C:40]([CH3:42])[C:39]([OH:43])=[C:38]([CH3:44])[CH:37]=3)[N:34]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(SC(C(=O)O)c2cccc(Cl)c2)cc1C
Reactant: Cc1cc(C(N)=NO)cc(C)c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(Cl)Cl
Product: Cc1ccc(SC(c2cccc(Cl)c2)c2nc(-c3cc(C)c(O)c(C)c3)no2)cc1C
Reaction time: 0.17 h

Procedure:
2-(3-Chlorophenyl)-2-((3,4-dimethylphenyl)thio)acetic acid (3.00 g, 9.78 mmol) was dissolved in dichloroethane, then carbonyldiimidazole (2.00 g, 12.35 mmol) was added, the resulting reaction mixture was stirred for 10 minutes, N′,4-dihydroxy-3,5-dimethylbenzimidamide crude (prepared according to Diana, Guy D et al. Journal of Medicinal Chemistry, 1994, vol. 37 (15) p. 2421-2436) (1.80 g, 9.99 mmol) was added. The reaction mixture was stirred for 30 minutes, then concentrated. Flash chromatography (40% EtOAc/Hex) gave the desired adduct which was dissolved in xylene (10 mL) and heated to 125° C. for 30 minutes, then cooled. Flash chromatography (20% EtAc/Hex) gave Intermediate 4.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Si:13]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH2:39][OH:40])[CH:35]=[C:36]([Cl:38])[CH:37]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:8][S:9]([O:40][CH2:39][C:34]1[CH:35]=[C:36]([Cl:38])[CH:37]=[C:32]([CH2:31][O:30][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(CO)c1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1cc(Cl)cc(COS(C)(=O)=O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (7.8 mL, 56 mmol) and methanesulfonyl chloride (2.9 mL, 37 mmol) were added to a solution of [3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorophenyl]methanol (7.65 g, 18.6 mmol, from Step 2) in DCM (50 mL) at 0° C. The cooling bath was removed and after reaction mixture warmed to room temperature, the reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with two further portions of DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-40% EtOAc/hexanes. Yield: (6.8 g, 75%).
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([CH:8]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(Cc1ccccc1)C(=O)O
Temperature: 0 °C

Procedure:
The methyl 2-benzyl-3-(t-butyldimethylsilyloxy)propionate (3.3 g) was dissolved in 100 ml of methanol, cooled to 0° C. and treated with 50 ml of 30% potassium hydroxide with vigorous stirring. The reaction was then allowed to warm to room temperature over five hours. The reaction was diluted with 200 ml of water, rinsed with diethyl ether, and the aqueous solution was cooled to 0° C. Dichloromethane (100 ml) was added, followed by the slow addition of 260 ml of 1M hydrochloric acid, with stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (3×200 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by radial chromatography (2% to 4% methyl alcohol in chloroform. 4 mm plate) to yield 2.14 9 of the 2-benzyl-3-(t-butyldimethylsilyloxy)propionic acid.