Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[OH:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 3 g (0.1 mole) of sodium hydride (80% in oil) and 50 ml of dimethylformamide (DMF), there are slowly added 15.4 g (0.1 mole) of 2,4-dihydroxybenzoic acid dissolved in 50 ml of DMF. The mixture is stirred at ambient temperature until the cessation of gaseous emission. There are then added 13.1 ml (0.1 mole) of benzyl bromide and the mixture is stirred at ambient temperature until solubilization of the reaction medium. The reaction mixture is poured into water, and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated- The residue is purified by chromatography on a silica column by eluting with dichloromethane. 19.7 g (81% yield) of the expected ester having a melting point of 94°-95° C. are recovered.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)acetic acid and t-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[C:18]=2[CH2:19][C:20]([OH:22])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:30][CH2:31][CH3:32]>>[ClH:1].[CH2:31]([N:30]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[C:20](=[O:22])[CH2:19][C:18]1[N:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]2=[N:10][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:32]
Reactant: CCNCc1ccccn1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)c(Cl)c3)nc2c1
Product: CCN(Cc1ccccn1)C(=O)Cc1c(-c2ccc(Cl)c(Cl)c2)nc2cc(C)ccn12
Product: Cl
Yield: 75.5 %

Procedure:
According to the method of Example 14, 2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(2-pyridinylmethyl)ethylamine were used as raw materials for synthesis, white solid powder, yield 75.5%. m.p. 217-220° C., ESI-MS m/z: 454[M+H]+, 1H NMR(DMSO-d6, 400 MHz)δ: 0.99(t, 1.5H, J=7.00 Hz), 1.25(t, 1.5H, J=7.00 Hz), 2.57(s, 1.5H), 2.60(s, 1.5H), 3.33(q, 1H, J=7.00 Hz), 3.65(q, 1H, J=7.00 Hz), 4.56(s, 1H), 4.59(s, 1H), 4.78(s, 1H), 4.86(s, 1H), 7.40-7.53(m, 1H), 7.54-7.68(m, 2H), 7.78-7.81(m, 1H), 7.89(s, 1H), 7.91-7.95(m, 1H), 8.62-8.67(m, 2H), 8.84-8.86(m, 2H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:39][C:36]3[N:35]=[CH:34][C:33]([C:31]([O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:32])=[CH:38][CH:37]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Nc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Yield: 14 %

Procedure:
The compound of example A8 was obtained by similar method described in example A1 using 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetic acid (Preparation 3, 0.150 g, 0.408 mmol), 6-aminopyridine-3-carboxylic acid tert-butyl ester (preparation 54, 0.095 g, 0.49 mmol), HOBT (0.082 g, 0.612 mmol), and EDCl (0.116 g, 0.612 mmol), N-methyl morpholine (0.103 g, 1.02 mmom) in DCM (4 mL) to provide the title compound (0.031 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClCCl.[Br:14]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe].O>[Br:14][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
139.40 g (64.7 mmol) of 4-nitrophenol and 130 ml of dichloromethane are introduced into a three-necked flask under an argon atmosphere. The mixture is cooled to 0° C. and 3.31 ml (67.7 mmol) of bromine are added dropwise. The reaction medium is stirred for one hour at 0° C., 360 mg (6.5 mmol) of iron powder are then added and this mixture is stirred for sixteen hours at room temperature. The reaction medium is poured into water, a saturated sodium thiosulphate solution is added, this mixture is extracted with dichloromethane and washed with water, the organic phase is separated out after settling has taken place and dried over magnesium sulphate, and the solvents are evaporated off. 13.50 g (96%) of the expected compound are collected in the form of a beige-coloured powder with a melting point of 105–107° C.
Reaction SMILES: [OH:1][C@@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[NH2:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15]>>[OH:1][C@@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15])=[O:5]
Reactant: C[C@](O)(C(=O)O)c1ccccc1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)[C@](C)(O)c2ccccc2)c2cccc(N)c2-c2ccccc21

Procedure:
Following one or more of the general procedures outlined above, using (R)-(−)-2-hydroxy-2-phenylpropionic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 458 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C@@H:30]([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C@@H:30]([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:7][C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 70 °C
Yield: 71.7 %

Procedure:
5-Chloro-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.8 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 4.45 g, 72%).
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-].[C:4]([OH:12])(=[O:11])[CH:5]([CH2:7][C:8]([OH:10])=[O:9])[OH:6]>O>[C:4]([O:12][OH:1])(=[O:11])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[Ca+2:2].[Ca+2:2].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6].[OH:1][O:11][C:4](=[O:12])[CH:5]([CH2:7][C:8]([O-:10])=[O:9])[OH:6]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: [OH-]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
A dicalciumhydroxy malate granular product was prepared by mixing two molar equivalents of particulate calcium hydroxide with one molar equivalent of particulate malic acid (totaling 45 kg for the entire composition) in a Ribbon Blender for 15 minutes at normal speeds. A water jacket was used to ensure that the product would not over react when small amounts of water were added to the batch. Next, about 1 L of water was slowly sprayed into the particulate mixture product. After about 10 minutes of reaction time (where the product became spongy and had risen, and then dropped back to a more granular state), an additional 1 L of water was added. This was repeated several times until no further reaction appeared to be occurring upon addition of water. The end result was a granular product. Once a fully reacted granular product was formed, no additional water was added. The resulting composition was then dried in a cool room and ground to a predetermined particle size.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(O)[C@@H:14]2[C:28]2[CH:33]=[CH:32][C:31]([CH:34]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=2)=[CH:8][CH:9]=1)=[O:4].C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[C:14]2[C:28]2[CH:29]=[CH:30][C:31]([CH:34]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:32][CH:33]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(O)C(C)(C)O[SiH2]C(C)(C)C)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: c1ccccc1
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(C(C)(C)O[SiH2]C(C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 23 (46 mg, 0.065 mmol) and methyl N-(triethylammoniumsulphonyl)carbamate (Burgess reagent, 62 mg, 0.26 mmol) in benzene (0.9 mL) was heated at 50° C. After 1 h, the reaction was quenched by addition of H2O and the resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/hexanes) gave compound 24 (31 mg, 68%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17](/[CH:21]=[CH:22]/[C:23]3[C:24]4[C:29]([N:30]=[C:31]5[C:36]=3[CH:35]=[CH:34][CH:33]=[CH:32]5)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[I:37][CH2:38][CH2:39][OH:40]>C(#N)C>[I-:37].[OH:40][CH2:39][CH2:38][N+:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23](/[CH:22]=[CH:21]/[C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]4[C:14]([C:15]=3[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[C:24]2[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]2
Reactant: OCCI
Reactant: COCCOCCn1c2ccccc2c2cc(/C=C/c3c4ccccc4nc4ccccc34)ccc21
Solvent: CC#N
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3c4ccccc4[n+](CCO)c4ccccc34)ccc21
Product: [I-]
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 12 (0.2 g, 0.4 mmol) and 2-iodoethanol (0.7 g, 4 mmol) in acetonitrile (10 mL) was heated to 120° C. in sealed tube for 24 h. After cooling down to room temperature, the solvent was removed and the resulting mixture was purified by precipitation from methanol and ethyl acetate to afford SAOH (0.13 g) in 52% yield. 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J=9.2 Hz, 2H), 8.77 (d, J=8.4 Hz, 2H), 8.44 (s, 1H), 8.36 (t, J=8.0 Hz, 2H), 8.18 (d, J=8.4 Hz, 1H), 8.17 (d, J=16 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.86 (t, J=8.0 Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.52 (t, J=6.4 Hz, 2H), 7.48 (d, J=16 Hz, 1H), 7.33 (t, J=6.4 Hz, 1H), 5.63 (t, J=6.0 Hz, 2H), 4.75 (t, J=7.6 Hz, 1H), 4.59 (t, J=6.0 Hz, 2H), 4.51-4.47 (m, 2H), 3.94 (t, J=6.0 Hz, 2H), 3.57-3.55 (m, 2H), 3.47-3.44 (m, 2H), 3.33 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 158.2, 149.1, 141.9, 140.7, 140.6, 138.1, 129.1, 126.9, 126.5, 126.4, 124.3, 123.3, 122.4, 121.2, 120.9, 120.0, 119.0, 117.0, 109.6, 109.2, 71.8, 70.6, 69.1, 59.3, 58.9, 52.2, 43.3. HRMS (MALDI-TOF) m/z Calcd for C34H33N2O3+ 517.2486 Found 517.2476 [M]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:6].N#N.Cl[C:32]1[CH:40]=[C:39](Cl)[CH:38]=[CH:37][C:33]=1C(Cl)=O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[N:12]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:33]=1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
Sodium Hydride (60% dispersion in oil, 80 mg, 1,5 mmol) was added to an ice-cold solution 5-Phenyl-3-phenylamino-thiophene-2-carboxylic acid methyl ester (2) (230 mg, 0,74 mmol) in 20 ml of N,N-dimethylformamide in an atmosphere of N2. After 5 min, 2,4-Dichloro-benzoyl chloride (310 mg, 1.48 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 16 h at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×10 mL) and the combined ether layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (30% EtOAc/Hexane) to obtain 58 mg (16%) of 3-[(2,4-Dichloro-benzoyl)-phenyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.65-7.10 ppm (m, 14H, Haro); 3.77 ppm (s, 3H).
Reaction SMILES: [S:1]1[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH:3]=[C:2]1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O.C(Cl)(Cl)Cl>CN(C)C=O>[S:1]1[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH:3]=[C:2]1[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2oc3ccccc3c2s1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2oc3ccccc3c2s1

Procedure:
A suspension of 15.5 g thieno[3,2-b]benzofuran-2-carboxylic acid, 16.9 g of thionyl chloride, 150 ml of chloroform and 1 ml of dimethylformamide is refluxed 5 hours, the reaction mixture is screened and the solvent removed from the filtrate to yield thieno[3,2-b]benzofuran-2-carboxylic acid chloride as a brown solid. 5.1 g of the above mentioned acid chloride is added portionwise over 30 minutes to a stirred mixture of 2.7 g of 2-aminothiophenol, 50 ml of toluene and 5 ml of pyridine cooled in an ice bath. The mixture is then stirred at ambient temperature for 17 hours, cooled, filtered and the residue washed with ligroin to yield the amide of formula (X) ##STR18## as a brown solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].[Br:21][CH:22]([CH2:24]Br)[CH3:23].O>ClCCl>[Br:21][C:22](=[CH2:23])[CH2:24][NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=1[O:10][CH3:9]
Reactant: CC(Br)CBr
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(Br)CNCc1ccc(OC)cc1OC
Reaction time: 18 h
Yield: 50.3 %

Procedure:
Triethylamine (16.0 mL, 114 mmol) was added to a solution of 2,4-dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and 2,3-dibromopropane (10.9 g, 54.5 mmol) in dichloromethane (200 mL). After 18 h, water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (7.85 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23](O)=[O:24])=[CH:22][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N+:34]=1[O-:43].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:35][N+:34]=3[O-:43])=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Reactant: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)c[n+]3[O-])c3c(c21)CC(C)(C)O3
Yield: 10.6 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-49, 0.100 g, 0.2564 mmol), thionyl chloride (2.0 mL), 2-amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.0835 g, 0.5128 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.49 (s, 2H), 3.53 (s, 3H), 7.02 (m, 1H), 7.18-7.36 (m, 3H), 7.80 (d, J=9.9 Hz, 1H), 8.64 (d, J=8.7 Hz, 1H), 8.95 (s, 1H), 10.56 (s, 1H), 12.21 (s, 1H); MS [M+H]+: 550.08.
Reaction SMILES: O(C([NH:8][C@@H:9]([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH3:19])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=O)C(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][C@@H:9]([C@H:18]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH3:19])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11]
Reactant: C[C@@H](c1ccc(F)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](c1ccc(F)cc1)[C@H](N)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product from Step A in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. After stirring at room temperature for 1 h, the solvent was removed in vacuo and the residue was purified by HPLC (YMC Pro-C18 column, gradient elution, 10-90% acetonitrile/water with 0.1% TFA) to give the title compound. LC/MS 269.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][NH:13][C:7]3([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:6][N:5]2[CH:22]=1.[CH3:23][N:24](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]23[NH:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]2[N:5]([CH:22]=[C:2]([C:23]#[N:24])[CH:3]=2)[CH2:6]3)=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C23Cn4cc(Br)cc4C(=O)N2CCN3)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(C23Cn4cc(C#N)cc4C(=O)N2CCN3)cc1
Temperature: 160 °C
Yield: 58 %

Procedure:
7-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (100 mg, 0.28 mmol), zinc cyanide (50 mg, 0.42 mmol) and palladium(0) tetrakistriphenylphosphine (32 mg, 0.03 mmol) were suspended in dry DMF (3 mL) in a microwave vial flushed with argon. The mixture was heated in the microwave reactor at 160° C. for 20 minutes. A saturated aqueous solution of NaHCO3 (50 mL) was added and the mixture extracted with CH2Cl2 containing 20% of isopropyl alcohol. The organic layers were dried (MgSO4), filtrated and concentrated in vacuo. The resulting residue was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient 0-5% methanol in CH2Cl2) to give 10a-(4-methoxyphenyl)-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carbonitrile (50 mg, yield 58%) ESI-MI m/z [M+H]+ 308.9. Used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[C:8]([F:32])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38]>>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[C:8]([F:32])=[CH:7][C:3]=1[C:4]([NH:38][CH2:37][CH2:36][C:35]([O:34][CH3:33])=[O:39])=[O:5].[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[C:8]([F:32])=[CH:7][C:3]=1[C:4]([NH:38][CH2:37][CH2:36][C:35]([OH:39])=[O:34])=[O:6]
Reactant: COCc1cc(-c2nc(-c3cc(F)c(C(=O)O)cc3F)no2)ccc1-c1ccccc1C
Reactant: COC(=O)CCN
Product: COCc1cc(-c2nc(-c3cc(F)c(C(=O)NCCC(=O)O)cc3F)no2)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cc(F)c(C(=O)NCCC(=O)OC)cc3F)no2)ccc1-c1ccccc1C

Procedure:
Methyl N-(2,5-difluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl)-beta-alaninate was prepared following the general procedure 14, starting from 2,5-difluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoic acid and beta-alanine methyl ester. It was hydrolyzed following general procedure 9 to afford the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 12.32 (brs, 1H), 8.68 (m, 1H), 8.33 (m, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.03 (m, 1H), 7.70 (m, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.39-7.25 (m, 3H), 7.15 (m, 1H), 4.20 (m, 2H), 3.48 (m, 2H), 3.25 (s, 3H), 2.53 (m, 2H), 2.03 (s, 3H). LC/MS (Method B): 508.0 (M+H)+, 506.1 (M−H)−. HPLC (Method B) Rt 4.83 min (Purity: 98%).