Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:13]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[O:11])[CH2:4][O:3]1.Cl>CO.O1CCOCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[N:20]([CH:21]2[CH2:22][CH2:23]2)[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2c(Nc3ccc(I)cc3F)c3cnccc3n2C2CC2)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NOCC(O)CO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5.2 %

Procedure:
To 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]-pyridine-2-carboxylic acid (2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (65.0 mg, 0.12 mmol) in anhydrous methanol (1.8 mL) was added 4 M Hydrogen chloride in 1,4-Dioxane (1.0 mL), and the reaction mixture was stirred at ambient temperature for 17 h. The solvent was removed in vacuo and the residue was redissolved in acetonitrile (2.0 mL) and loaded onto a Phenomenex Strata-X cartridge (5 g). The cartridge was washed with water (10 mL) and methanol (15 ml). The desired product was then eluted using 2M ammonia in MeOH. Methanol was removed in vacuo to give a brown oil, which was purified by HPLC to obtain 3.3 mg (5.5%) of the desired product as the TFA salt. 1H-NMR (500 MHz, MeOD.) δ ppm 8.96 (s, 1H), 8.45 (d, J=6.81 Hz, 1H), 8.18 (d, J=6.77 Hz, 1H), 7.48 (dd, J=10.76 Hz, 1H), 7.28 (d, J=8.50 Hz, 1H), 6.56 (t, J=9.6, 1H), 4.01-3.86 (m, 1H), 3.85-3.75 (m, 2H), 3.75-3.64 (m, 1H), 3.63-3.47 (m, 2H), 1.34-1.29 (m, 2H), 1.09-1.04 (m, 2H); LC-MS (method D): [M+H]+=527.0, RT=3.33 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[O:8])=[O:5])[CH3:2].[OH:9][C:10]1[N:14]=[C:13]([O:15][CH2:16][CH3:17])[S:12][N:11]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C:7]([N:11]1[C:10](=[O:9])[N:14]=[C:13]([O:15][CH2:16][CH3:17])[S:12]1)=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C=O
Reactant: CCOc1nc(O)ns1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)n1sc(OCC)nc1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
23 g of ethoxycarbonyl isocyanate were added dropwise to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 140 ml of tetrahydrofuran containing 1 ml of triethylamine and the mixture was stirred for 11/2 hours at 20° C and was filtered. The filtrate was concentrated to dryness and the residue was empasted with isopropyl ether and vacuum filtered. The product was crystallized from ethyl acetate to obtain 18 g of 2-(N-ethoxycarbonylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 119° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[N:16]=[C:17]([S:26][CH3:27])[N:18]=[N:19][C:20]=3[C:21](OCC)=[O:22])[CH:12]=2)[NH:7][CH:6]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[N:16]=[C:17]([S:26][CH3:27])[N:18]=[N:19][C:20]=3[C:21]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:22])[CH:12]=2)[NH:7][CH:6]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1nnc(SC)nc1Nc1ccc2[nH]cc(CCN(C)C)c2c1
Solvent: ClCCl
Product: CSc1nnc(C(=O)NCc2ccccc2)c(Nc2ccc3[nH]cc(CCN(C)C)c3c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22 %

Procedure:
To a stirred mixture of 3-(2-dimethylaminoethyl)-5-(6-ethoxycarbonyl-3-methylthio-1,2,4-triazin-5-ylamino)-1H-indole (0.25 g, 0.62 mmol) in methylene chloride (5 mL) at room temperature under nitrogen was added dropwise benzylamine (0.14 mL, 1.25 mmol, 2.0 eq). The resulting reaction mixture was stirred at room temperature under nitrogen for 48 hours, and then filtered. The resulting yellow solid was recrystallized from methanol: ethyl acetate (4:1) to afford the title compound (0.063 g, 22%) as a yellow solid: mp, 207.0°-209.0° C.; FAB HRMS calculated for [C24H27N7OS.H+ ]482.2079, found 462.2054. Anal. calcd. for C24H27N7OS.3/4 H2O: C, 60.67; H, 6.05; N, 20.63. Found: C, 60.58; H, 5.73; N, 20.58.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3]([CH:17]1[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:25])[CH2:16]1)=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1CCCc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C1CC(C(=O)C(F)(F)F)Cc2ccccc21
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one necked round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50 mL of ether was then added over about 5 min. The reaction mixture was then stirred at room temperature for 14 h and then was diluted with 100 mL of 3N HCl. The phases were separated and the organic layer washed with 3N HCl, brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo. The residue was then taken up in 70 mL of boiling ethanol/water and allowed to cool to room temperature whereupon crystals of 2-trifluoroacetyl-1-tetralone formed which were isolated by filtration and air dried to give 32 g, 81% of pure product with mp 48°-49° C. 1H NMR CDCl3 δ2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR CDCl3 δ72.0. EI GC-MS M+=242.
Reaction SMILES: [Cl:1]C(OCC)=O.[CH2:7]([S:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:16]=1[CH2:17]N(C)C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([S:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:16]=1[CH2:17][Cl:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(CN(C)C)c1SCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Product: COc1cccc(CCl)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Ethyl chloroformate (0.6 ml, 6.2 mmol) was added dropwise to an ice-cooled solution of 2-benzylthio-3-methoxy-N,N-dimethyl benzylamine (1.5 g, 5.2 mmol) in dry ether (40 ml). The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo, and the residual solid was extracted several times with hexane. The extracts were evaporated to leave the title compound as a solid (1.29 g, 89%), mp 54°-55C. (Found: C,64.67; H,5.50; Cl,12.99. C15H15ClOS requires C,64.62; H,5.42; Cl,12.72%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])C3SC=CN=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29].C(#N)C.NC1C(F)=C(F)C(F)=[C:44]2[C:39]=1[C:40](=O)[C:41](C(O)=O)=[CH:42][N:43]2[C@@H]1C[C@@H]1F>C(N(CC)CC)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])[C:41]3[CH:42]=[N:43][CH:44]=[CH:39][CH:40]=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: Nc1c(F)c(N2CC[C@@H](C(N)c3nccs3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3cccnc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 54.6 %

Procedure:
3-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl]pyrrolidine [F1] (70 mg, 0.252 mmol) was added to an acetonitrile suspension (3 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (87.0 mg, 0.275 mmol), and the mixture was heated under reflux for 19 hours in the presence of triethylamine (0.3 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (50 ml), this was washed with 10% citric acid (40 ml) and saturated brine (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (2 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (2 ml) at room temperature and then washed with chloroform (30 ml×4),and the insoluble matter was removed by filtration. This hydrochloric acid solution was adjusted to an alkaline liquid property by adding 10 mol/l sodium hydroxide aqueous solution. This suspension was adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×3). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol-aqueous ammonia to obtain 65.1 mg (54%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[CH:4][C:5]([F:14])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C1(C)C=CC=CC=1.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:14][C:5]1[CH:4]=[C:3]([F:15])[C:2]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)=[CH:7][C:6]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)c1cc(-c2ccncc2)c(F)cc1F
Temperature: 90 °C

Procedure:
5-Bromo-2,4-difluoro-N,N-dimethyl-benzenesulfonamide (400 mg) and 4-pyridine-boronic acid (165 mg) was dissolved in toluene (5 ml) and abs EtoH (5 ml). To the mixture was then added Na2CO3 (200 mg) and Pd(PPh3)4 (79 mg) under an atmosphere of Argon. The resulting mixture was heated to 90° C. for 18 h. Then CH2Cl2 was added and the organic phase was washed with water and dried (MgSO4), filtered and evaporated to dryness. The residue was then used without any further purification. (MS m/z (rel. intensity, 70 eV) 298 (M+, 77), 256 (36), 191 (bp), 190 (98), 143 (74).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH3:22])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc2c(ccn2Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 2-methylphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as a brown oil. Mass spectrum (ESI, [M+H]+) m/z 354. 1HNMR (400 MHz, DMSO-d6): δ 7.53 (d, 1H, J=3.06 Hz), 7.50 (d, 1H, J=8.55 Hz), 7.46 (d, 1H, J=0.95 Hz), 7.33 (d, 2H, J=7.96 Hz), 7.26-7.18 (m, 5H), 7.05 (d, 1H, J=8.40 Hz), 6.48 (d, 1H, J=3.06 Hz), 5.38 (s, 2H), 2.22 (s, 3H), and 1.22 ppm (s, 9H). Elemental Analysis for C26H27N: Calculated: C, 88.34; H, 7.70; N, 3.96. Found: C, 88.28; H, 7.58; N, 3.75.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([CH3:11])[N:5]=1.Cl[C:13]1[S:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:17]=1.Cl>C1COCC1>[Br:10][C:8]1[N:7]=[C:6]([CH3:11])[N:5]=[C:4]([NH:3][C:13]2[S:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:17]=2)[CH:9]=1
Reactant: COC(=O)c1cnc(Cl)s1
Reactant: Cc1nc(N)cc(Br)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Nc2cc(Br)nc(C)n2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
60% sodium hydride (12.0 g, 0.30 mol) was suspended in THF (300 mL) and cooled down to 0° C. 4-amino-6-bromo-2-methylpyrimidine (Compound 9) (18.7 g, 0.1 mol) was then added in batches and stirred for 30 min. After methyl 2-chlorothiazole-5-formate (Compound 10) (17.7 g, 0.1 mol) was added in batches, the reactants were heated and reacted by refluxing for 4 h, and then cooled down to room temperature for reaction overnight. When controlling the temperature between 0° C. and 5° C., hydrochloric acid (2N) was added for neutralization reaction. After adding keep heat and stirred to grow grains for 1 h. Filtrate and wash the cake with water, and then dry to give target Compound 11 (25.8 g, yield is 78.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40])[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: N#CCCCCBr
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCCCCC#N)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 99.9 %

Procedure:
Using 0.85 g (1.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 5-bromo-pentanenitrile (0.304 g, 1.88 mmol) and following the procedure of Example 42(b) afforded 1.0 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (3H, m), 1.4 (9H, s), 18 (7H, m), 2.6 (3H, m), 3.2 (1H, m), 3.7 (1H, m), 4.2 (2H, m), 6.76 (1H, d), 6.92 (1H, s), 7.14 (3H, m), 7.34 (1H, s), 7.88 (2H, d), 8.28 (1H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CC(O)=O.N.[N+:29]([CH3:32])([O-:31])=[O:30]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10](/[CH:11]=[CH:32]\[N+:29]([O-:31])=[O:30])=[CH:13][CH:14]=[CH:15][C:16]=1[N:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(C=O)c1OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)c1cccc(/C=C\[N+](=O)[O-])c1OCc1ccccc1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(benzyloxy)-3-(dimethylamino)benzaldehyde (5 g, 19.58 mmol, 1.00 equiv), acetic acid (40 mL), acetic acid amine (750 mg, 9.73 mmol, 0.50 equiv) and nitromethane (11.96 g, 195.94 mmol, 10.01 equiv). The resulting solution was stirred overnight at 105° C. in an oil bath. The resulting solution was diluted with 200 mL of ethyl acetate. The mixture was washed with NaOH (5 mol/L) until pH=7. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 3.5 g (60%) of 2-(benzyloxy)-N,N-dimethyl-3-[(Z)-2-nitroethenyl]aniline as a dark red solid. MS (ESI) m/z 299 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C[Al](C)C.C[O:15][C:16]([C:18]1[S:19][CH:20]=[C:21]([Br:24])[C:22]=1[CH3:23])=O>C(Cl)Cl>[Br:24][C:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:4][C:3]2[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])=[O:15])[S:19][CH:20]=1
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)c1scc(Br)c1C
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1c(Br)csc1C(=O)Nc1c(F)cccc1F
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a 0° C. solution of 2,6-difluoroaniline (1.10 g, 8.58 mmol, 1.0 eq) in DCM (20 mL) was added drop wise trimethyl aluminium (2 M in toluene, 4.3 mL, 1.0 eq) followed by a solution of methyl-4-bromo-3-methylthiophene-2-carboxylate (2.0 g, 8.58 mmol, 1.0 eq). The reaction was allowed to come to room temperature and then stirred for 2 h at the same temperature. The reaction was quenched with water (10 mL) followed by the addition of DCM (20 mL). The layers were separated, and the organic layer was washed with brine (15 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the residue was purified by flash column chromatography (silica gel, 30% ethyl acetate in hexane) to afford 1.0 g (35%) of the desired product as a brown solid. 1HNMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.28-7.21 (m, 1H), 7.15 (s, 1H, D2O exchangeable), 7.03-6.94 (m, 2H), 2.56 (s, 3H); ESI-MS (m/z) 332, 334 [(MH)+, Br79,81].
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].Cl[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCl>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])=[O:26]
Reactant: CCC(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(NC(=O)c1ccccc1Cl)C(=O)O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
This compound was prepared according to the procedures described in Int. J. Peptide Protein Res. 1989, 33, 353, and J. Chem. Soc., Chem. Commun. 1995, 2335. 2-Amino-butyric acid (3.87 g, 37.5 mmol) was suspended in 90 mL of dichloromethane, and treated with chloro-trimethyl-silane (9.6 mL, 75 mmol). The mixture was refluxed for 1 h and cooled in an ice bath. Diisopropylethylamine (11.3 mL, 65 mmol) and 2-chloro-benzoyl chloride (4.3 mL, 35.6 mmol) were added. The solution was stirred with cooling for 20 min and then warmed up to room temperature for 1.5 h. The mixture was concentrated and then distributed between ether and diluted NaHCO3 solution. The phases were separated. The aqueous layer was extracted with ether and the ether layer was back washed with water. The combined aqueous layers were acidified to pH 2 with 1N HCl and extracted with ethyl acetate three times. The combined ethyl acetate layers were dried over sodium sulfate, filtered and concentrated to give 2-(2-chloro-benzoylamino)-butyric acid as an off-white solid (7.0 g, 77% yield), which was used directly in the next step without further purification. LCMS calcd for C11H12ClNO3 (m/e) 241, obsd 242 (M+H).
Reaction SMILES: O[CH:2]([C:17]1[N:18]=[CH:19][N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:20]1[CH:21]=[C:17]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:18]=[CH:19]1
Reactant: N#Cc1ccc(-c2ccccc2C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccccc2Cc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2′-[Hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-biphenyl-4-carbonitrile (Intermediate D2) (2.4 g, 4.6 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with triethyl silane, Et3SiH (7.4 mL, 46 mmol) (commercially available from Aldrich) followed by trifluoroacetic acid, TFA (10.7 mL, 140 mmol) dropwise. After several minutes the cooling bath was removed and the mixture was stirred at rt for an additional 12 h. The reaction was quenched with solid NaHCO3 followed by aqueous workup. The layers were separated and the organic layers were combined and dried over Na2SO4. The mixture was filtered and concentrated to dryness. The residue was purified by chromatography on silica gel with 3% NH3-MeOH: CH2Cl2 to give the product 2′-(1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Intermediate D3), 0.74 mg, 62% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:13])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1
Reactant: C1CCNCC1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(C(=O)N3CCCCC3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (60 mg, 0.1415 mmol), 4-dimethylaminopyridine (8.6 mg, 0.0704 mmol) and piperidine (24 mg, 0.2823 mmol) were dissolved in methylene chloride (5 ml), WSC-HCl (81 mg, 0.4225 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (62 mg, 0.1265 mmol, 89%).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:12]([O-])=O)[C:5]([NH:15][CH:16]([CH2:18]C(OCC)=O)[CH3:17])=[CH:4][CH:3]=1.[Sn](Cl)Cl.[C:27](OCC)(=[O:29])C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[C:5]([NH:15][C:16]([CH3:17])([CH3:18])[C:27](=[O:29])[NH:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CC(C)Nc1ccc(Br)c(C(=O)OC)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(Br)ccc2c1NC(=O)C(C)(C)N2
Yield: 70 %

Procedure:
Methyl 6-bromo-3-[(2-ethoxycarbonyl)propan-2-yl]amino-2-nitrobenzoate (Reference Compound No. 1-(5), 105 mg, 0.26 mmol) was dissolved in anhydrous ethanol (4.5 mL), tin (II) chloride (247 mg, 1.30 mmol) was added thereto, and then the reaction mixture was refluxed for 5 hours. After the reaction mixture was cooled down, ethyl acetate (25 mL) was added thereto, the mixture was neutralized with aqueous sodium hydrogen carbonate solution, and then filtered on celite. After the filtrate was partitioned, the water layer was extracted with ethyl acetate (10 mL, twice), the combined organic layer was washed with water (50 mL, twice) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (56.3 mg) as a pale yellow solid. (Yield 70%)