Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH2:31][N:32]([C:11](=[O:13])[C:10]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=3)[CH:9]=2)[CH2:33][CH2:34]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(O)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 68.5 %

Procedure:
Following the procedure of Example 9(e) 3-(4-cyano phenoxy)-5-hydroxy benzoic acid 1.6 g (6.3 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (1.43 g, 6.27 mmol) were used to afford 2.0 g of the required product. Percentage purity (LCMS): 79.6%, (M+1)=465.2+1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].[Br:16]Br.S(=O)(=O)(O)[O-].[Na+]>[Fe](Cl)(Cl)Cl.O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A three neck flask was charged with 2-nitrobiphenyl (1 mol), iron trichloride (55 mmol), and water (200 mL) and set to stir under a nitrogen atmosphere for 30 minutes. Bromine (1.25 mol) was added dropwise over the course of one hour, then set to reflux for four hours, cooled to 60° C., and stirred for 12 hours. Sodium bisulfate (500 mmol) was added slowly, and the mixture rinsed three times with water (200 mL), twice with 5% sodium hydroxide solution (100 ml) and twice more with water (200 mL). The solids were dissolved in dichloromethane, dried over magnesium sulfate, and flashed chromatographed over silica with dichloromethane as the eluent. The solvent was removed under reduced pressure and the crude product recrystallized from ethanol to give 4′-bromo-2-nitrobiphenyl in 35% yield.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccccc2)cn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1ccc(-c2ccccc2)cn1)NO
Reaction time: 72 h
Yield: 7 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added the crude batch of III (16 mg) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×3 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:8 then 100:10) to furnish IV as a colourless oil (1.36 mg, 7% over two steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[CH:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:12]1[CH:11]=[CH:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc(=O)[nH]c2-c2ccc(F)cc2)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc(Cl)nc2-c2ccc(F)cc2)cc1
Temperature: 200 °C

Procedure:
A mixture of 1.00 g (2.92 mMol) of 6-(4-fluorophenyl)-1,2-dihydro-5-[4-(methylsulfonyl)phenyl]-2-oxopyridine from Step 8 and 25 ml of phosphorous oxychloride was heated in a bomb to 200° C. and maintained for 3 hours. After cooling, the mixture was evaporated to dryness. Chromatography of the residue over silica gel using 50% ethyl acetate/hexane as eluent gave 2-chloro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine (211 mg) as a pure white crystalline solid: m.p. 192° C. (DSC). Anal. Calc'd for C18H13ClFNO2S·.1/4 H2O (MW 366.33): C, 59.02; H, 3.58; N, 3.82. Found: C, 58.68; H, 3.65; N, 3.86.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:15][C:4]2[C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:30])([F:28])[F:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1Oc1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Oc1ccccc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-chloro-2-phenoxy-pyridin-3-ylamine (60 mg, 0.27 mmol) in anhydrous pyridine (0.5 mL) was added drop wise a solution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (76 mg, 0.27 mmol) in pyridine (0.5 mL). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.89-7.87 (m, 2H), 7.81 (m, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.25-7.19 (m, 2H), 6.76 (d, J=8.0 Hz, 2H). MS m/z: 463.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1.[CH:33]1([CH2:38][C:39](O)=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:33]1([CH2:38][C:39]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:22]([C:20]4[CH:21]=[C:16]([N:13]5[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]5)[N:17]=[C:18]([NH2:32])[N:19]=4)=[CH:23][CH:24]=3)[CH2:29]2)=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)CC1CCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCCC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (24 uL, 0.17 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (15 mg, 0.034 mmol), cyclopentaneacetic acid (5.2 uL, 0.041 mmol) (Aldrich, Cat. #125490), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (17 mg, 0.038 mmol) (Chem-Impex, Cat. #00604) in N,N-dimethylformate (0.5 mL). The mixture was stirred at r.t. for 30 min., and then purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=435.2.
Reaction SMILES: CC1C=[C:12]2[O:14]C=1C[C@H:5]([C:21](C)=C)[CH2:6][CH2:7][C:8]1C(=O)O[C@@H:10]([C@H:11]2C(C)=C)[CH:9]=1.[C:24]([O:28][C:29](=[O:42])[N:30]([C@H]1CC[C@H](C=C(Br)Br)CC1)[CH3:31])([CH3:27])([CH3:26])[CH3:25].[Li]CCCC.C=O>C1COCC1>[C:24]([O:28][C:29](=[O:42])[N:30]([C@H:6]1[CH2:5][CH2:21][C@H:9]([C:10]#[C:11][CH2:12][OH:14])[CH2:8][CH2:7]1)[CH3:31])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Reactant: C=C(C)[C@@H]1CCC2=C[C@@H](OC2=O)[C@@H](C(=C)C)c2cc(C)c(o2)C1
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 25 °C

Procedure:
The following reaction was performed in analogy to the reaction described in: Marshall, James A.; Bartley, Gary S.; Wallace, Eli M. Total Synthesis of the Pseudopterane (−)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B. J. Org. Chem. (1996), 61(17), 5729-5735 and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J. Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin Trans. 1 (1990), (5), 1415-21.). A solution of 993 mg (2.5 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 20 ml THF was treated at −78° C. with 3.28 ml (5.25 mmol) of BuLi (ca 1.6 M in hexane). After 2 h at this temperature 790 mg (25 mmol) of paraformaldehyde were added. The reaction mixture was warmed up to RT for 3 h and after 1 h at this temperature extracted with water/ether (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 4:1) yielded 530 g (79%) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 268 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([OH:11])[CH:4]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:4]=1
Reactant: COCCOCCl
Reactant: COc1ccc(C=O)c(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1cc(OC)ccc1C=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4-methoxy-2-hydroxybenzaldehyde (6.5 g, 40 mmol), MEM-chloride (10.0 g, 80 mmol) and diisopropylethylamine (21 mL, 120 mmol) in dichloromethane (200 mL) was stirred at 25° C. for 14 h. The reaction mixture was concentrated to a small volume, diluted with diethyl ether (200 mL) and filtered through a short path of silica gel. The filtrate was concentrated to give crude 4-methoxy-2-(methoxyethoxy)methoxy-benzaldehyde which was pure enough for use in the next step.
Reaction SMILES: [OH-].[K+].Cl.[CH2:4]([O:6][C:7]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]([C:17]([O:19]CCC)=[O:18])[C:8]=1[C:23]1[C:28]([C:29]([O:31]C)=[O:30])=[CH:27][C:26]([O:33][CH3:34])=[C:25]2[O:35][CH2:36][O:37][C:24]=12)[CH3:5]>O1CCOCC1>[CH2:4]([O:6][C:7]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]([C:17]([OH:19])=[O:18])[C:8]=1[C:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]([O:33][CH3:34])=[C:25]2[O:35][CH2:36][O:37][C:24]=12)[CH3:5]
Reactant: CCCOC(=O)c1cc(OC)c(OC)c(OCC)c1-c1c(C(=O)OC)cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1c(OC)c(OC)cc(C(=O)O)c1-c1c(C(=O)O)cc(OC)c2c1OCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In 4 ml of dioxane was dissolved in 48 mg of methyl 2-ethoxy-2',3'-methylenedioxy-6-propoxycarbonyl-3,4,4'-trimethoxy-1,1'-biphenyl-6'-carboxylate obtained in Example 9, and 1 ml of a 5% aqueous solution of potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight, the pH value was adjusted to 1 by 3N hydrochloric acid, and the mixture was extracted with chloroform. The solvent was removed from the extract to obtain 36 mg of 2-ethoxy-2',3'-methylenedioxy-3,4,4'-trimethoxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:39]4[C:34]([Cl:33])=[N:35][CH:36]=[CH:37][CH:38]=4)=[O:41])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a stirred solution of 6.06 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 10 ml of N,N-diisopropylethylamine is added a solution of 4.0 g of 2-chloropyridine-3-carbonyl chloride in 25 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with water and the organic layer washed well with water. The organic layer is dried, filtered and evaporated in vacuo to a pale yellow product which is crystallized from 1:1 ethyl acetate:hexane to give 7.0 g of the desired product; M+ =442.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O:11][C:12](=O)[C:13](=O)[CH3:14])C>C(O)C>[CH3:14][C:13]1[C:12](=[O:11])[NH:7][C:2]2[C:1]([N:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: Cc1nc2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzene-1,2-diamine (10.8 g, 100 mmol) in ethanol (500 mL) was treated with a solution of ethyl-2-oxopropanoate (11.22 g, 110 mmol) slowly at 0° C., and the resulting suspension was stirred at room temperature for 1 h, then filtered. An off-white solid was collected (15.85 g). MS (ESI): m/z 161 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=2>ClCCl>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCl
Product: CCOCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of ethoxyacetyl chloride (4.2 g, 34 mmol) in dichloromethane was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (5.1 g, 29 mmol) in dichloromethane (75 mL), and the reaction was stirred for one hour at room temperature. Additional ethoxyacetyl chloride (0.5 g, 4 mmol) was added, and the reaction was stirred for 30 minutes and diluted with dichloromethane (75 mL). The resulting mixture was washed with saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, and filtered. Methanol was added to facilitate the filtration. The filtrate was concentrated under reduced pressure to provide 7.3 g of N-(4-chloroquinolin-3-yl)-2-ethoxyacetamide as a dark solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:31]#[N:32])[CH2:23][C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Na+].[CH3:34][S:35]([O-])(=[O:37])=[O:36]>CS(C)=O.CCOC(C)=O.[Cu](I)I>[C:31]([C@@H:22]([NH:21][C:19](=[O:20])[C@@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:26][CH:25]=1)#[N:32]
Reactant: CS(=O)(=O)[O-]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(I)cc1
Agent: I[Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]-L-leucinamide (1 eq) in DMSO (0.3 M) were added methane sulfonic acid sodium salt (2 eq) and copper iodide (3 eq) and the mixture was stirred at 100° C. for 2 h. The reaction mixture was cooled and diluted with EtOAc. The organic layer was washed with brine and water, dried over Na2SO4, filtered and concentrated. The crude compound was purified by automated SiO2 flash chromatography system using solvent gradient of 40% EtOAc/Hex to 100% EtOAc/Hex.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:26]=[CH:25][C:15]([CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:14][CH:13]=2)[N:11]=1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]1[CH2:3][CH:2]1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:25][CH:26]=2)[N:11]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2csc(NC(=O)C3CC3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2csc(NC(=O)C3CC3)n2)cc1
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 4-[(2-cyclopropanecarbonyl-amino)-thiazol-4-yl]-N-(tert-butoxycarbonyl)-benzylamine (2.381 g, 6.376 mmol) in anhydrous DCM (53 mL), add trifluoroacetic acid (45 mL) at room temperature and stir overnight. Concentrate the reaction mixture in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, add silica gel (14 g) and concentrate to a powder. Load the powder on to a dry column attached to an Analogix® column (150 g) and purify by preparative liquid chromatography (0:1 to 1:4 2M ammonia in methanol/DCM over 33 min, 1:4 2M ammonia in methanol/DCM over 33 min; 35 mL/min) to afford the title compound (1.668 g, 96%) as an off-white solid. MS (ES+) m/z: 274.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[O:33]=[C:28]1[NH:29][C:30](=[O:32])[C:31](=[CH:25][C:22]2[CH:21]=[CH:20][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:3]([CH2:1][CH3:2])[C:4](=[O:11])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:14]=3)=[CH:24][CH:23]=2)[S:27]1
Reactant: CCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Reactant: O=C1CSC(=O)N1
Product: CCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Yield: 85.4 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 300 mg (0.9 mmol) of N-ethyl-N-(4′-formyl-biphenyl-3-ylmethyl)benzamide with 100 mg (0.9 mmol) of 2,4-thiazolidine dione, 340 mg (88%) of the expected product are obtained.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:12]C(=O)OC(C)(C)C)[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1.O>Cl>[CH:1]1([CH2:4][C@H:5]([NH2:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc([C@H](CC2CC2)NC(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: O
Product: Cc1nc([C@@H](N)CC2CC2)no1
Yield: 74.8 %

Procedure:
A solution of (S)-tert-butyl 2-cyclopropyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethylcarbamate (0.5 g, 2 mmol) in sat. hydrochloric acid (10 mL) was stirred at room temperature for 1 h. Then water (20 mL) was added. The water phase was washed with ethyl acetate (2×20 mL) and adjusted with 2 M sodium hydroxide solution to pH=9-10. It was then extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give crude product as a white solid (0.25 g, 80%); MS (EI): m/e 168.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:33]([N:35]([CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1)[CH2:36][CH3:37])[CH3:34]
Reactant: CCNCC
Reactant: COc1ccc(-c2c(C(=O)CC(C)C)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Product: CCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)CC(C)C

Procedure:
According to the same manner as that described in Example 1, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxyquinoline was reacted with diethylamine to give 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl) -3-isovaleryl-6,7-dimethoxyquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 153°-154° C.
Reaction SMILES: Cl.[C:2]1([C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:5])[OH:3].[CH3:10][C:11]([CH3:13])=O>>[CH3:10][C:11]1([CH3:13])[O:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[O:3]1
Reactant: Oc1ccccc1O
Reactant: CC(C)=O
Agent: Cl
Product: CC1(C)Oc2ccccc2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
Hydrogen chloride gas was introduced into a solution of 110.1 g of pyrocatechol in 370 ml of acetone for 2 hours while stirring and cooling with ice 10°-15° C. internal temperature, and then for an additional 30 minutes at 0° C. The mixture was poured into ice/water, made alkaline and extracted three times with 1 l of ether. The organic phase was washed neutral three times with 500 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue was distilled in vacuo (b.p. 11 mm/59°-60° C.). There were obtained 39.0 g (26.0% of theory) of 2,2-dimethyl-1,3-benzodioxole.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:1]([O:9][CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)c(F)cc1C(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C=O)c1cc(F)c(F)cc1C(=O)COC(=O)c1ccccc1

Procedure:
A solution of benzoic acid (40.3 g) and triethylamine (61 ml) in dichloromethane (200 ml) was added dropwise over 20 minutes to the solution of 2'-(2-chloroacetyl)-4',5'-difluoro-N-methylformanilide at 0° under nitrogen and the resultant solution stirred overnight at ambient temperature. The mixture was washed with water (3×250 ml) and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel eluted with dichloromethane:methanol (50:1) to give the novel compound 2-[4,5-difluoro-2-(N-methylformamido)phenyl-2-oxoethyl benzoate in the form of an oil.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>N1C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([Cl:14])=[O:11])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=Cc1ccc(C(=O)Cl)cc1

Procedure:
To 7.50 g of terephthalaldehydic acid (4-formylheuzoic acid) were added 20 ml of thionyl chloride and 1 ml of pyridine, followed by heating under stirring. After the reaction mixture became clear, stirring was further continued at reflux for 4 hours, followed by allowing to cool. The excess thionyl chloride was removed by distillation under reduced pressure, toluene was added to the residue, and any insoluble matter was separated by filtration. The toluene was removed from the filtrate by distillation to obtain 7.91 g of 4-formylbenzoyl chloride.