Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[Mg]Br.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH3:11][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: CCOC(=O)Cl
Reactant: c1ccc2cnccc2c1
Solvent: C1CCOC1
Product: CCOC(=O)N1C=Cc2ccccc2C1c1c(C)cc(C)cc1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-mesitylmagnesium bromide in THP (1.0 M, 11 mL; 11 mmol) was added to an ice-cold solution of isoquinoline (1.3 g, 10 mmol) in THF (10 ml). After 5 minutes, ethyl chloroformate was added slowly dropwise and the mixture was further stirred at 0° for 10 min before quenched by saturated NH4CL solution. The mixture was poured into 0.5 N hydrochloric acid and extracted twice with ethyl ether. Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 3.58 g of titled compound (quantitative) as an oil which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[Cl:11][C:12]([Cl:16])=[C:13]([F:15])[F:14].C(N(CC)CC)C>O>[Cl:11][C:12]1([Cl:16])[CH:7]([C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:8][C:13]1([F:15])[F:14]
Reactant: FC(F)=C(Cl)Cl
Reactant: C=Cc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2CC(F)(F)C2(Cl)Cl)cc1

Procedure:
p-Methoxystyrene (40.8 g., 0.30 mole), 1,1-dichloro-2,2-difluoroethylene (55.8 g., 0.42 mole), and triethylamine (3.0 ml., 0.02 mole) are heated in a sealed tube (25 × 615 mm) at 125°-130°C. for 16 hrs. The cooled mixture is then poured into water, the reaction product extracted with ether, and the extracts washed with water, dried (MgSO4), and evaporated to an oil. Distillation of the oil yields 69.0 g. (86%), b.p. 80°-85°C. (0.1 mm), of the desired intermediate suitable for use in the next step. Part of the oil was chromatographed (alumina, cyclohexane), and redistilled, b.p. 81°C. (0.02 mm), nD27 1.5207.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+].[CH:22](=O)[CH2:23][CH3:24]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCNCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In methanol (6.0 ml), (4-amino-butyl)-carbamic acid t-butyl ester (400.0 mg) was dissolved. After acetic acid (0.12 ml) and sodium cyanoborohydride (172.5 mg) were added to the solution, propionaldehyde (0.155 ml) was dropped thereto and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (339.6 mg) as a colorless oily substance.
Reaction SMILES: [CH2:1](C1C=C(C(OCOC)(C(F)(F)F)C(F)(F)F)C=C(CCC)C=1O)CC.ClC1C=C(B(O)O)C=CN=1.Cl[C:38]1[CH:43]=[C:42]([O:44][C:45]2[C:50]([CH2:51][CH2:52][CH3:53])=[CH:49][C:48]([C:54]([O:63]COC)([C:59]([F:62])([F:61])[F:60])[C:55]([F:58])([F:57])[F:56])=[CH:47][C:46]=2[CH2:67][CH2:68][CH3:69])[CH:41]=[CH:40][N:39]=1.[CH3:70][C:71]1([C:78]2[CH:83]=[CH:82][C:81]([O:84][CH:85]([CH3:87])[CH3:86])=[CH:80][CH:79]=2)[NH:75][C:74](=[O:76])[NH:73][C:72]1=[O:77]>>[F:56][C:55]([F:57])([F:58])[C:54]([C:48]1[CH:47]=[C:46]([CH2:67][CH2:68][CH3:69])[C:45]([O:44][C:42]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:1][N:73]3[C:72](=[O:77])[C:71]([C:78]4[CH:83]=[CH:82][C:81]([O:84][CH:85]([CH3:87])[CH3:86])=[CH:80][CH:79]=4)([CH3:70])[NH:75][C:74]3=[O:76])[CH:43]=2)=[C:50]([CH2:51][CH2:52][CH3:53])[CH:49]=1)([OH:63])[C:59]([F:62])([F:61])[F:60]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1O
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1Oc1ccnc(Cl)c1
Agent: OB(O)c1ccnc(Cl)c1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(CCC)c1Oc1ccnc(CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)c1

Procedure:
2,6-dipropyl-4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]phenol was used in place of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenol, and 2-chloropyridine-4-boronic acid was used in place of 3-(hydroxymethyl)phenylboronic acid in Preparation Example 3 for a similar reaction and treatment, and the obtained 2-chloro-4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2,6-dipropylphenoxy) pyridine and 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione were used for a similar reaction and treatment as Example 40, and the title compound was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([Li])(CC)C.[C:15](=[O:17])=[O:16].Cl>C1COCC1.CCCCCC>[OH:6][CH:5]1[C:4]2[C:3](=[C:2]([F:1])[CH:9]=[CH:8][CH:7]=2)[C:15](=[O:16])[O:17]1
Reactant: O=C=O
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1OC(O)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a -70° C. solution of the dimethylacetal of 3-fluorobenzaldehyde (5.3 g, 31 mmol) in THF (35 ml) was added dropwise sec-butyllithium (22.2 ml of a 1.4 M solution in hexane), and the red solution was stirred for 0.5 h. The solution was saturated with CO2 for 5 min with tne red color dissipating to yield a light yellow solution. After 10 min the reaction was allowed to warm to room temperature, and after 30 min HCl (3.5 ml) was added. After concentration the solution was made basic with 5% KOH (25 ml), the neutral material extracted with Et2O (2×40 ml), the base layer acidified to pH 1 witn HCl, and the product extracted with EtOAc (2×75 ml). Work up as usual afforded 4.5 g (86%) of the title compound, mp 11°-119°, suitable for use in the next step. Recrystallization of this material from EtOAc/PE gave analytically pure material: mp 126°-127° C.; IR 3400 (br s), 1740-1760 (structured s), 1630 (m), 1485 (m), 1300 (m), 1085 (s), 910 (m), 760 (m); 1H NMR 7.8-7.1 (highly structured m, 3 H), 6.60 (br s, 1H); exact mass calcd for C8H5O3F m/e 168.0227, obsd 168.0226.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[ClH:19].[Cl:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[OH-:29].[K+]>O.C1(C)C=CC=CC=1.ClC1C=CC=CC=1>[ClH:20].[ClH:19].[O:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][O:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12](=[O:16])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:21][CH2:22][N:23]5[CH2:28][CH2:27][O:29][CH2:25][CH2:24]5)[CH:10]=4)[C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:24][CH2:25]1
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Reactant: [OH-]
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1c2ccc(OCCN3CCOCC3)cc2C(=O)c2ccc(OCCN3CCOCC3)cc21

Procedure:
This compound was prepared by the method of Example 3, with the exception that toluene was used as the reaction medium rather than chlorobenzene, from 36 g. (0.15 mole) of 2,6-dihydroxyanthraquinone, 100 g. (0.54 mole of N-(2-chloroethyl) morpholine hydrochloride, 66g. (1.0 mole) of potassium hydroxide pellets (85%), 400 ml. of toluene and 100 ml. of water. The dihydrochloride salt was recrystallized twice from isopropanol with enough water added to effect solution. The pure compound melted with decomposition at 288°-290°C.; γmax (H2O) 273 mμ, E1cm1% 778.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+].[CH:16](Cl)(Cl)Cl>C(O)C.O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[O:14])[C:10]([OH:13])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(Cl)Cl
Reactant: [OH-]
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=Cc1cc(-c2ccccc2)ccc1O
Reaction time: 3 h

Procedure:
22 g of p-phenylphenol was dissolved in 95% ethanol; a solution of 40 g of sodium hydroxide in 80 ml of water was rapidly added. The resulting solution was heated to 75°-80° C. and 20 ml of chloroform was added over a one-hour period, the mixture being gently refluxed. The mixture then was stirred for three hours, cooled and the ethanol and excess chloroform were evaporated under reduced pressure. The resulting residue was cooled and poured into cold water. The resulting mixture was acidified by slow addition of hydrochloric acid and extracted with ether. The solvent was evaporated from the extract under reduced pressure, the residue was poured in twice its volume of saturated sodium metabisulfite solution and the mixture was shaken vigorously for forty-five minutes. The resulting semisolid bisulfite addition compound was allowed to stand for one hour, filtered in the dark and washed with small portions of ethanol and ether to remove the phenol. The bisulfite addition compound was decomposed with dilute sulfuric acid, the mixture being warmed on a water-bath for thirty minutes. The cooled mixture was extracted with ether. The extract was dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was treated with activated charcoal and recrystallized from ethanol/water to give 5-phenylsalicylaldehyde (5A) as yellow crystals, mp: 98°-99° C.
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:32])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1.CO>CC(CC)=O>[ClH:1].[CH3:32][N:8]([CH3:7])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccc(F)cc2)CC1
Solvent: CO
Solvent: CCC(C)=O
Solvent: O
Product: Cl

Procedure:
Chlorotrimethylsilane (0.118 ml) and water (8 μl) were added to a solution of the less polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-(4-fluoro-phenyl)-acetamide (300 mg, 0.8 mmol) in ethyl methyl ketone (2 ml) and a little methanol. After concentration it was possible to isolate the hydrochloride in a yield of 397 mg (quantitative) (Example 57).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>>[CH2:10]([NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCCN
Product: CCCNc1ccc(C#N)cc1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 4-fluorobenzonitrile and n-propylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC1CCNC(=O)CC1N
Product: CC1CCNC(=O)CC1NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-4-methyl-ε-caprolactam (General Procedure—C), the title compound was prepared as a mixture of diasteromers. The reaction was monitored by tlc on silica gel (Rf=0.18 in 5% MeOH/dichloromethan).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[CH:34]([O:37][C:38]([O:40][CH:41](I)[CH3:42])=[O:39])([CH3:36])[CH3:35].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:41]([O:40][C:38]([O:37][CH:34]([CH3:36])[CH3:35])=[O:39])[CH3:42])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Reactant: CC(C)OC(=O)OC(C)I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)OC(=O)OC(C)OC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 1-(isopropyloxycarbonyloxy)ethyl iodide (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (85 mg) was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)[CH3:2].[H][H]>[Pd].CO>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:18]
Reactant: CCN(CC)CC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CC1CCNC1
Reaction time: 20.3 h
Yield: 101.7 %

Procedure:
A mixture of 25.4 g (0.10 mole) of N,N-diethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 200 ml of methyl alcohol, 2 g of palladium on carbon and hydrogen were shaken at a pressure of 51.5 psi. After 20.3 hours, the catalyst was filtered and the filtrate concentrated under reduced pressure. The residue was bulb to bulb distilled giving 15.9 g of N,N-diethyl-3-pyrrolidinemethanamine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:12][C:13](=[O:14])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH:6]3[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.BrC1C=C2C3=C(NC(=O)N3C(C3C=CC=CC=3)CC2)C=1.[CH3:41][C:42]1[C:46](B(O)O)=[C:45]([CH3:50])[O:44][N:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[CH3:41][C:42]1[C:46]([C:2]2[CH:11]=[CH:10][C:9]3[NH:12][C:13](=[O:14])[N:7]4[C:8]=3[C:3]=2[CH2:4][CH2:5][CH:6]4[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:45]([CH3:50])[O:44][N:43]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CC3
Agent: O=C([O-])[O-]
Agent: O=c1[nH]c2cc(Br)cc3c2n1C(c1ccccc1)CC3
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1CCC3c1ccccc1
Temperature: 90 °C
Yield: 56.1 %

Procedure:
A mixture of 7-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (0.050 g, 0.15 mmol) (4.4:1 mixture of isomers with 8-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one as the minor isomer), (3,5-dimethylisoxazol-4-yl)boronic acid (10.7 mg, 0.0759 mmol), and cesium carbonate (99.0 mg, 0.304 mmol) in 1,2-dimethoxyethane (1.21 mL) and water (0.303 mL) was degassed with nitrogen for 5 min. The reaction mixture was treated with PEPPSI-IPr (5.2 mg, 0.0076 mmol) [Aldrich, cat. #669032], degassed with nitrogen for 5 min, and heated at 90° C. for 1 h. The reaction mixture was then diluted with ethyl acetate (25 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (14.7 mg, 28%) as a racemic mixture. 1H NMR (500 MHz, CDCl3) δ 10.00 (s, 1H), 7.34-7.20 (m, 3H), 7.08-6.95 (m, 3H), 6.88-6.76 (m, 1H), 5.54 (s, 1H), 2.45-1.96 (m, 10H); LCMS calculated for C21H20N3O2 (M+H)+: m/z=346.2. found: 346.1.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:12]=1[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.P([O-])(O)(O)=[O:25].[Na+].Cl([O-])=O.[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:12]=1[C:13]([OH:25])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1sc(-c2ccccc2)cc1C=O
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)c1sc(-c2ccccc2)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of 3-Formyl-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester (300 mg, 1.04 mmol) in dry THF (20 ml), at 0° C., under nitrogen, was treated with methyl sulfide (10% w/w in THF, 3.8 ml, 5.2 mmol) followed by sodium dihydrogenphosphate (30% aqueous solution, 9.56 ml, 2.05 mmol). After 0.5 h, the solution was treated with sodium chlorite (30% w/w aqueous solution, 1.9 ml, 2.08 mmol) added over 1 min via a syringe. The pale yellow solution was stirred for 1.5 h at 0° C., then diluted with water (20 ml) and extracted with EtOAc (4×40 ml). The aqueous phase was separated, extracted with more EtOAc (40 ml) and the combined extracts were washed with brine dried and concentrated to give 316 mg (100%) of 5-Phenyl-thiophene-2,3-dicarboxylic acid 2-tert-butyl ester as a pale brown solid. NMR 1H (CD3CO; 400 MHz): 7.87 (s, 1H); 7.83-7.81 (m, 2H); 7.17-7.53 (m, 3H); 1.65 (bs, 9H).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C(OCC)(=O)C>ClC(Cl)C>[CH2:13]([N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: C1=C(c2ccccc2)CCN(Cc2ccccc2)C1
Yield: 50 %

Procedure:
1,2,3,6-Tetrahydro-4-phenylpyridine (410 mg, 2.6 mmol), benzaldehyde (300 mg, 2.9 mmol), sodium triacetoxyborate (1.1 g, 5.2 mmol) and acetic acid (1.5 ml, 26 mmol) were stirred in dichloroethane at a room temperature for 14 hours. To the reaction solution was added ethyl acetate, and the resulting solution was washed with sodium hydroxide aqueous solution (1 N) and saturated brine and dried with anhydrous sodium sulfate. Then the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was separated and purified by a silica gel column chromatography to obtain 330 mg of the title compound (1.3 mmol, 45% in yield).
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:14][C:13]=3[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:10][N:9]([CH3:30])[C:8]=12.Cl>CO>[CH3:30][N:9]1[C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][C:7]=2[C:11]([C:12]2[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])[CH:15]=[CH:14][C:13]=2[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:10]1
Reactant: COc1nccc2c(-c3cc(CS(C)(=O)=O)ccc3Nc3ccccn3)cn(C)c12
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2cc(CS(C)(=O)=O)ccc2Nc2ccccn2)c2cc[nH]c(=O)c21
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
A mixture of Example 203A (0.062 g, 0.147 mmol) in methanol (1 mL) was treated with hydrogen chloride solution (4 M in 1,4-dioxane, 1 mL, 4 mmol) and heated at 75° C. for 2.5 hours. Additional hydrogen chloride solution (4 M in 1,4-dioxane, 1 mL, 4 mmol) was added and heating was continued for another 3.5 hours. The reaction mixture was then concentrated and the residue was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm) A gradient of 20-100% acetonitrile (A) and 10 mM ammonium acetate in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 20% A, 0.5-7.0 minutes linear gradient 20-95% A, 7.0-10.0 minutes 100% A, 10.0-12.0 minutes linear gradient 100-20% A to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (d, J=5.19 Hz, 1H), 8.08 (m, 1H), 7.98 (d, J=8.24 Hz, 1H), 7.89 (s, 1H), 7.47 (m, 1H), 7.42 (s, 1H), 7.34 (d, J=2.14 Hz, 1H), 7.27 (dd, J=8.24, 2.14 Hz, 1H), 6.79 (dd, J=6.71, 5.80 Hz, 1H), 6.76 (d, J=8.24 Hz, 1H), 6.70 (m, 1H), 6.25 (d, J=6.71 Hz, 1H), 4.45 (s, 2H), 4.09 (s, 3H), 2.93 (s, 3H). MS (ESI+) m/z 409.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:22])=[C:16]([F:24])[CH:15]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Br)cc2F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromo-2-fluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (15.1 mg) with purity >90%. MS (pos) m/z 423.3, 425.3.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C1CCNCC1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](N=C=O)[CH:32]=[CH:33][CH:34]=1.N.[N-:41]=[C:42]=[O:43]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH:17][C:42]([NH:41][C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=3)=[O:43])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: [N-]=C=O
Agent: N
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)Nc1ccc(C(F)(F)F)cc1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (14.8 mg, 0.05 mmol) in CHCl3 (2 mL) was treated with (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g), 3-(trifluoromethyl)phenyl isocyanate (1.3 equiv.) and stirred at 25° C. for 16 h. (Aminomethyl)polystyrene was added to scavenge the residual isocyanate and the reaction mixture was stirred at 25° C. for 16 h. Filtration and concentration afforded 1-(4-chlorobenzyl)-4-[{2-(3-(4-trifluoromethylphenyl)ureido)acetylamino}methyl]piperidine (19 mg, 78%) (compound No. 852): The purity was determined by RPLC/MS (92%); ESI/MS m/e 483 (M++H, C23H26ClF3N4O2).
Reaction SMILES: ClC1C=CC(C2OC3C=CC=CC=3C=2)=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]3[CH:53]=[CH:52][CH:51]=[CH:50][C:38]=3[C:39]=2[C:40](=[O:49])[C:41]2[CH:46]=[CH:45][C:44]([O:47]C)=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]3[CH:53]=[CH:52][CH:51]=[CH:50][C:38]=3[C:39]=2[C:40](=[O:49])[C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: Clc1ccc(-c2cc3ccccc3o2)cc1
Product: O=C(c1ccc(O)cc1)c1c(-c2ccc(Cl)cc2)oc2ccccc12

Procedure:
Acylation of 2-(4-chlorophenyl)benzofuran with p-anisoyl chloride followed by demethylation of the 2-(4-chlorophenyl)-3-(4-methoxybenzoyl)benzofuran thus formed by procedures described above gives 2-(4-chlorophenyl)-3-(4-hydroxybenzoyl)benzofuran.